Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs

Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases.

Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may contribute to pathology in some cases. Autophagy degrades many of the toxic, aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others, raising the possibility that autophagy upregulation may help to reduce levels of toxic protein species, and thereby alleviate disease. This review examines autophagy induction as a potential therapy in several neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Evidence in cells and in vivo demonstrates promising results in many disease models, in which autophagy upregulation is able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression. However, the effective therapeutic use of autophagy induction requires detailed knowledge of how the disease affects the autophagy-lysosome pathway, as activating autophagy when the pathway cannot go to completion (e.g., when lysosomal degradation is impaired) may instead exacerbate disease in some cases. Investigating the interactions between autophagy and disease pathogenesis is thus a critical area for further research

Neurobiology of axonal transport defects in motor neuron diseases: opportunities for translational research?

Intracellular trafficking of cargoes is an essential process to maintain the structure and function of all mammalian cell types, but especially of neurons because of their extreme axon/dendrite polarisation. Axonal transport mediates the movement of cargoes such as proteins, mRNA, lipids, membrane-bound vesicles and organelles that are mostly synthesised in the cell body and in doing so is responsible for their correct spatiotemporal distribution in the axon, for example at specialised sites such as nodes of Ranvier and synaptic terminals. In addition, axonal transport maintains the essential long-distance communication between the cell body and synaptic terminals that allows neurons to react to their surroundings via trafficking of for example signalling endosomes. Axonal transport defects are a common observation in a variety of neurodegenerative diseases, and mutations in components of the axonal transport machinery have unequivocally shown that impaired axonal transport can cause neurodegeneration (Reviewed in El-Kadi et al., 2007, De Vos et al., 2008; Millecamps and Julien, 2013). Here we review our current understanding of axonal transport defects and the role they play in motor neuron diseases (MNDs) with a specific focus on the most common form of MND, amyotrophic lateral sclerosis (ALS)

Endoplasmic reticulum dysfunction in neurological disease.

Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible

Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate protein structure and function. Dysregulated PTMs may influence the propensity for protein aggregation in NDD-proteinopathies. To investigate this, we systematically reviewed the literature to evaluate effects of PTMs on aggregation propensity for major proteins linked to the pathogenesis and/or progression of NDDs. A search of PubMed, MEDLINE, EMBASE, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between PTMs and protein aggregation in seven NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, transmissible spongiform encephalopathy, and multiple sclerosis. Together, 1222 studies were identified, of which 69 met eligibility criteria. We identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD; acetylation, 4-hydroxy-2-neonal modification, O-GlcNAcylation or phosphorylation of α-synuclein in PD; acetylation or phosphorylation of TAR DNA-binding protein-43 in ALS, and SUMOylation of superoxide dismutase-1 in ALS; and phosphorylation of huntingtin in HD. The potential pharmacological manipulation of these aggregation-modulating PTMs represents an as-yet untapped source of therapy to treat NDDs

Autophagy, cellular aging and age related human diseases

Macroautophagy/autophagy is a conserved degradation system that engulf s i ntracytoplasmic contents, including aggregated proteins and organelles , which is crucial for cellular homeostasis. During aging, cellular factors suggested as the cause of aging have been reported to be associated with prog ressive ly compromised autophagy. D ysfunctional autophagy may contribute to age related diseases such as neurodegenerative disease, cancer, and metabolic syndrome in the elderly Therefore, restoration of impaired autophagy to normal may help to prevent age related disease and extend lifespan and longevit y. Therefore, this review aims to provide an overview of the mechanism s of autophagy machinery underlying cellular aging and the consequent disease Understanding the mechanisms of autophagy can provide potential information to aid therapeutic intervention s in age related diseases.We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), Roger de Spoelberch Foundation, Alzheimer’s Research UK, The Tau Consortium, Cambridge Centre for Parkinson-Plus, National Institute for Health Research Cambridge Biomedical Research Centre (D.C.R.), and the Korea Health Technology R&D Project (HI14C2173) through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (S.Y.C., H. K., and J.E.L)

The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway.

The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases