Alzheimer’s disease (AD) is one of the world’s most pressing health crises. AD is an incurable disease affecting more than 6.5 million Americans, predominantly the elderly, and in its later stages, leads to memory loss, dementia, and death. Amyloid β (Aβ) protein aggregates have been one of the pathological hallmarks of AD since its initial characterization. The early stages of Aβ accumulation and aggregation involve the formation of oligomers, which are considered neurotoxic and play a key role in further aggregation into fibrils that eventually appear in the brain as amyloid plaques. We have recently shown by combining ion mobility mass spectrometry (IM-MS) and atomic force microscopy (AFM) that Aβ42 rapidly forms dodecamers (12-mers) as the terminal oligomeric state, and these dodecamers seed the early formation of Aβ42 protofibrils. The link between soluble oligomers and fibril formation is one of the essential aspects for understanding the root cause of the disease state and is critical to developing therapeutic interventions. Utilizing a joint pharmacophore space (JPS) method, potential drugs have been designed specifically for amyloid-related diseases. These small molecules were generated based on crucial chemical features necessary for target selectivity. In this paper, we utilize our combined IM-MS and AFM methods to investigate the impact of three second-generation JPS small-molecule inhibitors, AC0201, AC0202, and AC0203, on dodecamer as well as fibril formation in Aβ42. Our results indicate that AC0201 works well as an inhibitor and remodeler of both dodecamers and fibril formation, AC0203 behaves less efficiently, and AC0202 is ineffective.

Exosomes are shown to be involved in the regulation of neuroinflammatory injury. The current study analyzed how peripheral blood-derived exosomes affected hyaluronan-binding protein 2 (HABP2) expression to regulate neuroinflammatory injury after ischemic stroke (IS). An IS animal model was stimulated by middle cerebral artery occlusion (MCAO), followed by injection of lentivirus. Peripheral blood samples were collected from MCAO mice after different treatments. The cerebral infarction volume, astrocyte activation, and neuroinflammation were observed by TTC staining, immunofluorescence, and ELISA, respectively. HABP2 was highly expressed in the brain tissues of MCAO mice. Also, an enhancement of HABP2 was noted in their peripheral blood-derived exosomes, while loss of HABP2 in peripheral blood-derived exosomes promoted the astrocyte autophagy and reduced the release of the inflammatory factors as well as the apoptosis of neuronal cells. PAR1 overexpression reversed the effect of HABP2 loss on autophagy and neuroinflammation in MCAO mice. Additionally, the agonist of the PI3K/AKT/mTOR pathway, SC79, could also reverse the effect of sh-PAR1 on neuroinflammation. Mechanistically, HABP2 enhanced PAR1 to activate the PI3K/AKT/mTOR pathway, thereby suppressing cell autophagy. Overall, HABP2 in peripheral blood-derived exosomes can activate the PAR1/PI3K/AKT/mTOR pathway to reduce autophagy and aggravate neuroinflammatory injury after IS.

Parkinson’s disease (PD), a progressive neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder is caused primarily by the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately, there are no therapeutic agents that slow or delay the disease progression. Herein, menstrual stromal cell-derived dopamine-like neurons (DALNs) intoxicated with paraquat (PQ2+)/maneb (MB) were used as a model system to elucidate the mechanism by which CBD protects the neural cell from apoptosis in vitro. According to immunofluorescence microscopy, flow cytometry, cell-free assay, and molecular docking analysis, we demonstrate that CBD offers protection to DALNs against PQ2+ (1 mM)/MB (50 μM)-induced oxidative stress (OS) by simultaneously (i) decreasing reactive oxygen species (ROS: O2•–, H2O2), (ii) maintaining the mitochondrial membrane potential (ΔΨm), (iii) directly binding to stress sensor protein DJ-1, thereby blunting its oxidation from DJ-1CYS106-SH into DJ-1CYS106-SO3, and (iv) directly binding to pro-apoptotic protease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling. Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independent of CB1 and CB2 receptor signaling. CBD also re-established the Ca2+ influx in DALNs as a response to dopamine (DA) stimuli under PQ2+/MB exposure. Because of its powerful antioxidant and antiapoptotic effects, CBD offers potential therapeutic utility in the treatment of PD.

Chronic traumatic encephalopathy (CTE), a unique tauopathy, is pathologically associated with the aggregation of hyperphosphorylated tau protein into fibrillar aggregates. Inhibiting tau aggregation and disaggregating tau protofibril might be promising strategies to prevent or delay the development of CTE. Newly resolved tau fibril structures from deceased CTE patients’ brains show that the R3-R4 fragment of tau forms the core of the fibrils and the structures are distinct from other tauopathies. An in vitro experiment finds that epigallocatechin gallate (EGCG) can effectively inhibit human full-length tau aggregation and disaggregate preformed fibrils. However, its inhibitive and destructive effects on the CTE-related R3-R4 tau and the underlying molecular mechanisms remain elusive. In this study, we performed extensive all-atom molecular dynamics simulations on the CTE-related R3-R4 tau dimer/protofibril with and without EGCG. The results reveal that EGCG could reduce the β-sheet structure content of the dimer, induce the dimer to form loosely packed conformations, and impede the interchain interactions, thus inhibiting the further aggregation of the two peptide chains. Besides, EGCG could reduce the structural stability, decrease the β-sheet structure content, reduce the structural compactness, and weaken local residue–residue contacts of the protofibril, hence making the protofibril disaggregated. We also identified the dominant binding sites and pivotal interactions. EGCG preferentially binds with hydrophobic, aromatic, and positively/negatively charged residues of the dimer, while it tends to bind with polar, hydrophobic, aromatic, and positively charged residues of the protofibril. Hydrophobic, hydrogen-bonding, π–π stacking, and cation−π interactions synergistically drive the binding of EGCG on both the dimer and the protofibril, but anion−π interaction only exists in the interaction of EGCG with the dimer. Our work unravels EGCG’s inhibitive and destructive effects on the CTE-related R3-R4 tau dimer/protofibril and the underlying molecular mechanisms, which provides useful implications for the design of drugs to prevent or delay the progression of CTE.

The gastrointestinal (GI) system is affected in Alzheimer’s disease (AD); however, it is currently unknown whether GI alterations arise as a consequence of central nervous system (CNS) pathology or play a causal role in the pathogenesis. GI mucus is a possible mediator of GI dyshomeostasis in neurological disorders as the CNS controls mucus production and secretion via the efferent arm of the brain–gut axis. The aim was to use a brain-first model of sporadic AD induced by intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg) to dissect the efferent (i.e., brain-to-gut) effects of isolated central neuropathology on the GI mucus. Morphometric analysis of goblet cell mucigen granules revealed altered GI mucus secretion in the AD model, possibly mediated by the insensitivity of AD goblet cells to neurally evoked mucosal secretion confirmed by ex vivo cholinergic stimulation of isolated duodenal rings. The dysfunctional efferent control of the GI mucus secretion results in altered biochemical composition of the mucus associated with reduced mucin glycoprotein content, aggregation, and binding capacity in vitro. Finally, functional consequences of the reduced barrier-forming capacity of the mucin-deficient AD mucus are demonstrated using the in vitro two-compartment caffeine diffusion interference model. Isolated central AD-like neuropathology results in the loss of efferent control of GI homeostasis via the brain–gut axis and is characterized by the insensitivity to neurally evoked mucosal secretion, altered mucus constitution with reduced mucin content, and reduced barrier-forming capacity, potentially increasing the susceptibility of the STZ-icv rat model of AD to GI and systemic inflammation induced by intraluminal toxins, microorganisms, and drugs.

Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and N-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure–activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 and Emax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound’s activity), serotonin was included as a second reference agonist, and the compounds’ activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure–activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both “benchmark bias” (relative to LSD) and “physiology bias” (relative to serotonin).

Ras homolog gene family member (RhoA) is a GTPase and a member of the RAS superfamily of GTPases. RhoA is a master regulator of the actin cytoskeleton. It inhibits axon growth preventing repair and recovery following spinal cord and traumatic brain injuries. Despite decades of research into the biological function of Rho GTPases, there exist no small-molecule Rho inhibitors. Here, we screen a library of cysteine electrophiles to explore whether covalent bond formation at Cys-107 leads to inhibition of RhoA activation by guanine exchange factor Trio. Two fragments, propiolamide 1 (ACR-895) and acrylamide 2 (ACR-917), inhibited RhoA nucleotide exchange by Trio in a time-dependent manner. The fragments formed a covalent bond with wild-type RhoA but not Cys107Ser RhoA mutant. Time- and concentration-dependent studies led to equilibrium constants KIs and reaction rates that correspond to t1/2 values in the single-digit hour range. One fragment was selective for RhoA over Rac1 GTPase and had no effect on KRAS nucleotide exchange by SOS1. The fragments did not inhibit RhoA binding to ROCK effector protein. This work establishes Cys-107 as a suitable site for Rho GTPase inhibition and provides fragment starting points for the future development of Rho GTPase covalent inhibitors that could have profound implications in the treatment of patients with injuries of the central nervous system.

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer’s disease. Based on proteolysis-targeting chimera (PROTAC) technology, a small set of novel GSK-3β degraders was designed and synthesized by linking two different GSK-3β inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound 1 emerged as the most effective PROTAC being nontoxic up to 20 μM to neuronal cells and already able to degrade GSK-3β starting from 0.5 μM in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by Aβ25–35 peptide and CuSO4 in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC 1 may serve as a starting point to develop new GSK-3β degraders as potential therapeutic agents.

Epstein–Barr virus (EBV) is known to be associated with several cancers along with neurological modalities like Alzheimer’s disease (AD) and multiple sclerosis (MS). Previous study from our group revealed that a 12 amino acid peptide fragment (146SYKHVFLSAFVY157) of EBV glycoprotein M (gM) exhibits amyloid-like self-aggregative properties. In the current study, we have investigated its effect on Aβ42 aggregation along with its effect on neural cell immunology and disease markers. EBV virion was also considered for the above-mentioned investigation. An increase in the aggregation of Aβ42 peptide was observed upon incubation with gM146–157. Further, the exposure of EBV and gM146–157 onto neuronal cells indicated the upregulation of inflammatory molecules like IL-1β, IL-6, TNF-α, and TGF-β that suggested neuroinflammation. Besides, host cell factors like mitochondrial potential and calcium ion signaling play a crucial role in cellular homeostasis and alterations in these factors aid in neurodegeneration. Changes in mitochondrial membrane potential manifested a decrease while elevation in the level of total Ca2+ ions was observed. Amelioration of Ca2+ ions triggers excitotoxicity in neurons. Subsequently, neurological disease-associated genes APP, ApoE4, and MBP were found to be increased at the protein level. Additionally, demyelination of neurons is a hallmark of MS and the myelin sheath consists of ∼70% of lipid/cholesterol-associated moieties. Hereby, genes associated with cholesterol metabolism indicated changes at the mRNA level. Enhanced expression of neurotropic factors like NGF and BDNF was discerned postexposure to EBV and gM146–157. Altogether, this study delineates a direct connection of EBV and its peptide gM146–157 with neurological illnesses.

Neuropeptides with the C-terminal Wamide (Trp-NH2) are one of the last common ancestors of peptide families of eumetazoans and play various physiological roles. In this study, we sought to characterize the ancient Wamide peptides signaling systems in the marine mollusk Aplysia californica, i.e., APGWamide (APGWa) and myoinhibitory peptide (MIP)/Allatostatin B (AST-B) signaling systems. A common feature of protostome APGWa and MIP/AST-B peptides is the presence of a conserved Wamide motif in the C-terminus. Although orthologs of the APGWa and MIP signaling systems have been studied to various extents in annelids or other protostomes, no complete signaling systems have yet been characterized in mollusks. Here, through bioinformatics, molecular and cellular biology, we identified three receptors for APGWa, namely, APGWa-R1, APGWa-R2, and APGWa-R3. The EC50 values for APGWa-R1, APGWa-R2, and APGWa-R3 are 45, 2100, and 2600 nM, respectively. For the MIP signaling system, we predicted 13 forms of peptides, i.e., MIP1–13 that could be generated from the precursor identified in our study, with MIP5 (WKQMAVWa) having the largest number of copies (4 copies). Then, a complete MIP receptor (MIPR) was identified and the MIP1–13 peptides activated the MIPR in a dose-dependent manner, with EC50 values ranging from 40 to 3000 nM. Peptide analogs with alanine substitution experiments demonstrated that the Wamide motif at the C-terminus is necessary for receptor activity in both the APGWa and MIP systems. Moreover, cross-activity between the two signaling systems showed that MIP1, 4, 7, and 8 ligands could activate APGWa-R1 with a low potency (EC50 values: 2800–22,000 nM), which further supported that the APGWa and MIP signaling systems are somewhat related. In summary, our successful characterization of Aplysia APGWa and MIP signaling systems represents the first example in mollusks and provides an important basis for further functional studies in this and other protostome species. Moreover, this study may be useful for elucidating and clarifying the evolutionary relationship between the two Wamide signaling systems (i.e., APGWa and MIP systems) and their other extended neuropeptide signaling systems.

The role of cyclin-dependent kinase 5 (Cdk5) in the normal functioning of the central nervous system and synaptic plasticity is well established. However, dysregulated kinase activity can have a significant impact on neurodegeneration and cognitive impairment. Cdk5 hyperactivation is linked to diabetes-associated neurodegeneration, but the underlying mechanism is not fully understood. Our study reveals that oxidative stress can lead to Cdk5 hyperactivity, which in turn is linked to neurodegeneration and cognitive impairment. Specifically, our experiments with N2A cells overexpressing Cdk5 and its activators p35 and p25 show ER stress, resulting in activation of the unfolded protein response (UPR) pathway. We identified Cdk5 as the epicenter of this regulatory process, leading to the activation of the CDK5-IRE1-XBP1 arm of UPR. Moreover, our study demonstrated that Cdk5 hyperactivation can lead to ER stress and activation of the UPR pathway, which may contribute to cognitive impairments associated with diabetes. Our findings also suggest that antioxidants such as NAC and GSH can decrease deregulated Cdk5 kinase activity and rescue cells from UPR-mediated ER stress. The accumulation of phosphorylated Tau protein in AD brain protein has been widely described earlier. Notably, we observed that oral treatment with NAC decreased Cdk5 kinase activity in the hippocampus, attenuated high levels of phospho-tau (ser396), and ameliorated memory and learning impairments in a type 2 diabetic (T2D) mouse model. Additionally, the high-fat-induced T2D model exhibits elevated phospho-tau levels, which are rescued by the NAC treatment. Taken together, these results suggest that targeting Cdk5 may be a promising therapeutic strategy for treating diabetes-associated cognitive impairments.

Mutations in the proline-rich domain (PRD) of annexin A11 are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, and generate abundant neuronal A11 inclusions by an unknown mechanism. Here, we demonstrate that recombinant A11-PRD and its ALS-associated variants form liquidlike condensates that transform into β-sheet–rich amyloid fibrils. Surprisingly, these fibrils dissolved in the presence of S100A6, an A11 binding partner overexpressed in ALS. The ALS variants of A11-PRD showed longer fibrillization half-times and slower dissolution, even though their binding affinities for S100A6 were not significantly affected. These findings indicate a slower fibril-to-monomer exchange for these ALS variants, resulting in a decreased level of S100A6-mediated fibril dissolution. These ALS-A11 variants are thus more likely to remain aggregated despite their slower fibrillization.

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

Aggregation of mutant huntingtin is a pathological hallmark of Huntington’s disease (HD). Protein aggregation results in various cellular dysfunctions, such as increase in oxidative stress, mitochondrial damage, proteostasis imbalance, etc., which finally cause cell death. Previously, specific RNA aptamers with high affinity for mutant huntingtin were selected. In the current study, we show that the selected aptamer inhibits aggregation of mutant huntingtin (EGFP-74Q) in HEK293 and Neuro 2a cell models of HD. The presence of aptamer decreases sequestration of chaperones and increases their cellular levels. This is accompanied by improved mitochondrial membrane permeability, reduced oxidative stress, and increased cell survival. Thus, RNA aptamers can be explored further as inhibitors of protein aggregation in protein misfolding diseases.

Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation yet to take place. Here we describe the synthesis of fluorinated 5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM) and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorination with non-decay-corrected radiochemical yields of 15 ± 6% and 18 ± 2% over 85 and 80 min, respectively, with high radiochemical purities (>97%) and molar activities (140–416 GBq/μmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

Activin A (Act A) is a member of the transforming growth factor-β (TGF-β) superfamily and can protect against ischemic cerebral injury. Ferroptosis, a newly discovered type of programmed cell death, contributes to the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). However, little is known on whether Act A can modulate neuronal ferroptosis to protect against CIRI in a mouse model of middle cerebral artery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The results indicated that Act A treatment relieved CIRI by improving neurological deficits and reducing the infarct volume in mice. MCAO stimulated iron accumulation and malondialdehyde formation and upregulated ACSL4 expression but downregulated GPX4 expression, a hallmark of ferroptosis in the brain of mice. Treatment with Act A significantly mitigated MCAO-triggered ferroptosis in the brain of mice. Furthermore, Act A treatment enhanced the MCAO-upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression in the brains of mice. Similar results were observed in HT22 cells following OGD/R and pretreatment with Act A. The neuronal protective effect of Act A in HT22 cells was attenuated by treatment with ML385, an Nrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2 expression and inhibiting neuronal ferroptosis.

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer’s disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.

Information about the rates of hydrolysis of neuropeptides by extracellular peptidases can lead to a quantitative understanding of how the steady-state and transient concentrations of neuropeptides are controlled. We have created a small microfluidic device that electroosmotically infuses peptides into, through, and out of the tissue to a microdialysis probe outside the head. The device is created by two-photon polymerization (Nanoscribe). Inferring quantitative estimates of a rate process from the change in concentration of a substrate that has passed through tissue is challenging for two reasons. One is that diffusion is significant, so there is a distribution of peptide substrate residence times in the tissue. This affects the product yield. The other is that there are multiple paths taken by the substrate as it passes through tissue, so there is a distribution of residence times and thus reaction times. Simulation of the process is essential. The simulations presented here imply that a range of first order rate constants of more than 3 orders of magnitude is measurable and that 5–10 min is required to reach a steady state value of product concentration following initiation of substrate infusion. Experiments using a peptidase-resistant d-amino acid pentapeptide, yaGfl, agree with simulations.

Parkinson’s disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.

Fatigue is a common symptom in neurological diseases with a complex cause, involving the influence of events occurring in both the central and peripheral nervous systems. When people suffer from fatigue, a general decline in their movement performance typically occurs. The neural representation of dopamine signaling in the striatum plays a crucial role in movement regulation. Movement vigor is regulated by dopamine-dependent neuron activity in the striatum. However, whether exercise-induced fatigue alters stimulated dopamine release and further affects movement vigor has not been described. Here, for the first time, we used fast-scan cyclic voltammetry to demonstrate the effect of exercise-induced fatigue on stimulated dopamine release in the striatum in combination with a fiber photometry system to observe the excitability of striatal neurons. The movement vigor of mice was reduced, and after fatigue, the balance of excitability of striatal neurons regulated by dopamine projections was disturbed, which was induced by a reduction in dopamine release. Additionally, D2DR regulation may serve as a targeted intervention to alleviate exercise-induced fatigue and promote fatigue recovery.