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Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β -sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons. Neurodegenerative disease: Clearing out the clumps Strategies for speeding up the removal of misfolded proteins could counter the devastating effects of various neurological disorders. Cells have many ways of ‘taking out the garbage’, but these can become impeded in diseases such as Alzheimer's, where brain cells accumulate toxic clumps of misfolded proteins. Aaron Ciechanover and Yong Tae Kwon of Seoul National University in South Korea review how these clearance pathways get thwarted in neurodegenerative conditions associated with protein aggregation. Cellular quality control mechanisms deteriorate with age. However, some diseases directly interfere with cellular machinery. For example, in Parkinson's disease, aggregates of the α-synuclein protein cause ‘traffic jams’ in a cellular mechanism responsible for eliminating misfolded proteins. Drugs that selectively stimulate these removal processes offer hope, and the authors highlight promising early data from animal studies.

Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer’s disease (AD), impairments in the movement, Parkinson’s disease (PD), and the inability to walk, talk, and think, Huntington’s disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases.

Mutated HTT , resulting in mutant huntingtin, causes Huntington’s disease. A phase 1–2a trial of intrathecal delivery of an antisense oligonucleotide targeting HTT mRNA in 34 persons with Huntington’s disease showed a dose-dependent reduction of mutant huntingtin in cerebrospinal fluid and no serious adverse events in those who received the drug.

In many repeat diseases, such as Huntington’s disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats. Naphthyridine-azaquinolone specifically binds slipped-CAG DNA intermediates, induces contractions of expanded repeats and reduces mutant HTT protein aggregates in cell and animal models of Huntington’s disease.

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.

Tominersen and Huntington’s DiseaseA trial of tominersen, designed to slow Huntington’s disease progression by lowering levels of huntingtin protein, was stopped prematurely, and an ad hoc analysis of the results at week 69 was carried out.

Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were –4·6 for valbenazine and –1·4 for placebo (least-squares mean difference –3·2, 95% CI –4·4 to –2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Neurocrine Biosciences.

Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin ( HTT ) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels. Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin ( HTT ) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an  HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion. Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.