ALS: a disease of motor neurons and their nonneuronal neighbors.

ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure.

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

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Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.

Modulation of neurodegeneration by molecular chaperones.

Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases.

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The Biology of Proteostasis in Aging and Disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.

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Olga Schagina

Papers

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy

Deletions in AZFc Region of Y Chromosome in Russian Fertile Men