Neurodegenerative diseases as proteinopathies-driven immune disorders

In the pathophysiology of neurodegenerative disorders,the role of misfolded protein deposition leading to neurodegeneration has been primarily discussed.In the last decade,however,it has been proposed a parallel involvement of innate immune activation,chronic inflammation and adaptive immunity in the neurodegeneration mechanisms triggered by proteinopathies.New insights in the neurodegenerative field strongly suggest a role for the immune system in the pathophysiology of neurodegenerative disorders.Therefore,the hypothesis underlining the modulation of the innate and the adaptive immune system in the events linked to brain deposition of misfolded proteins could open new perspectives in the setting of specific immunotherapeutic strategies for the treatment of neurodegenerative diseases.Therefore,we have reviewed the pathogenic hypothesis in neurodegenerative pathologies,underling the links between the deposition of misfolded protein mechanisms and the immune activation.

Mitochondrial quality control in amyotrophic lateral sclerosis：towards a common pathway？

Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.

Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases

Cells have different sets of molecules for performing an array of physiological functions.Nucleic acids have stored and carried the information throughout evolution,whereas proteins have been attributed to performing most of the cellular functions.To perform these functions,proteins need to have a unique conformation and a definite lifespan.These attributes are achieved by a highly coordinated protein quality control(PQC)system comprising chaperones to fold the proteins in a proper threedimensional structure,ubiquitin-proteasome system for selective degradation of proteins,and autophagy for bulk clearance of cell debris.Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery,leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions.However,modulating the expression and functional efficiency of molecular chaperones,E3 ubiquitin ligases,and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects.Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions.The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.

Beyond the synucleinopathies:alpha synuclein as a driving force in neurodegenerative comorbidities

The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted fact.A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain.Beyond the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease.In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception,the potential role that aSyn may have in these disorders has received relatively little attention.In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities.In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies,we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins,including tau,TDP-43,amyloid-βand prion protein,in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology.We conclude that a growing body of evidence,encompassing neuropathology studies in human brain,animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction,cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities.We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.

Expression of human FUS protein in Drosophila leads to progressive neurodegeneration

Mutations in the Fused in sarcoma/Translated in liposarcoma gene(FUS/TLS,FUS)have been identified among patients with amyotrophic lateral sclerosis(ALS).FUS protein aggregation is a major pathological hallmark of FUS proteinopathy,a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies.We prepared transgenic Drosophila expressing either the wild type(Wt)or ALS-mutant human FUS protein(hFUS)using the UAS-Gal4 system.When expressing Wt,R524S or P525L mutant FUS in photoreceptors,mushroom bodies(MBs)or motor neurons(MNs),transgenic flies show age-dependent progressive neural damages,including axonal loss in MB neurons,morphological changes and functional impairment in MNs.The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy,representing the first stable animal model for this group of devastating diseases.

FUS/TLS forms cytoplasmic aggregates,inhibits cell growth and interacts with TDP-43 in a yeast model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a fatal disease characterized by the premature loss of motor neurons.While the underlying cellular mechanisms of neuron degeneration are unknown,the cytoplasmic aggregation of several proteins is associated with sporadic and familial forms of the disease.Both wild-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS patients.It is not known if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic aggregates.Here we present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in which toxicity is associated with greater expression and accumulation of FUS in cytoplasmic aggregates.We find that FUS and TDP-43 have a high propensity for co-aggregation,unlike the aggregation patterns of several other aggregation-prone proteins.Moreover,the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins,suggesting they are not composed of amyloid.

A new method for quantifying mitochondrial axonal transport

Axonal transport of mitochondria is critical for neuronal survival and function. Automatically quantifying and analyzing mitochondrial movement in a large quantity remain challenging. Here, we report an efficient method for imaging and quantifying axonal mitochondrial trans- port using microfluidic-chamber-cultured neurons together with a newly developed analysis package named ＂MitoQuant＂. This tool-kit consists of an automated program for tracking mitochondrial movement inside live neuronal axons and a transient-velocity analysis program for analyzing dynamic movement patterns of mitochondria. Using this method, we examined axonal mitochondrial movement both in cultured mammalian neurons and in motor neuron axons of Drosophila in vivo. In 3 different paradigms （temperature changes, drug treatment and genetic manipulation） that affect mitochondria, we have shown that this new method is highly efficient and sensitive for detecting changes in mitochondrial movement. The method significantly enhanced our ability to quantitatively analyze axonal mitochondrial movement and allowed us to detect dynamic changes in axonal mltochondrial transport that were not detected by traditional kymographic analyses.