Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis

  title={Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis},
  author={Justin J. Yerbury and Natalie E. Farrawell and Luke McAlary},
  journal={Trends in Neurosciences},

High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS)

For ALS-associated mutant proteins that do cause reductions in protein quality control capacity, such as SOD1A4V, this assay has potential to be applied in drug screening studies to identify candidate compounds that can ameliorate this deficiency.

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

The observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS.

From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis

The most significant contributions of omics technologies in unraveling the biological heterogeneity of ALS are discussed, highlighting how these approaches are revealing diagnostic, prognostic and therapeutic targets for future personalized interventions.

Destination Amyotrophic Lateral Sclerosis

A philosophical understanding of how early leads are crucial to understanding the endpoints in ALS is provided, because invariably, all early symptomatic leads are underpinned by neurodegeneration at the cellular, molecular and genomic levels.

ALS sensitive spinal motor neurons enter a degenerative downward spiral of impaired splicing and proteostasis

A protocol to differentiate CrMNs and SpMNs from human induced pluripotent stem cells (iPSCs) by direct programming and positional patterning is optimized, finding that ALS-sensitive iSpMNs appear to enter a downward spiral compromising their ability to maintain proteostasis and splicing.



Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

The evidence linking dysfunctional proteostasis to the etiology of ALS and how ALS-associated insults affect the protestasis network are reviewed and the potential therapeutic benefit of proteostatic network modulation in ALS is discussed.

Proteostasis disturbance in amyotrophic lateral sclerosis

Functional studies in various ALS models are revealing a complex scenario where distinct and even opposite effects in disease progression are observed depending on the targeted component of the proteostasis network, representing one of the earliest defects observed in disease models.

Decoding ALS: from genes to mechanism

Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified, and emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking.

Failure to Deliver and Translate—New Insights into RNA Dysregulation in ALS

Recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis are reviewed.

Walking the tightrope: proteostasis and neurodegenerative disease

The role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways, and the active formation of inclusions, in neurodegenerative diseases associated with protein aggregation are discussed.

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

The results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.

Changes in proteome solubility indicate widespread proteostatic disruption in mouse models of neurodegenerative disease

The data suggest that neurodegenerative proteinopathies modeled in mice impose a burden on the proteostatic network that diminishes the ability of neural cells to prevent aberrant conformational changes that alter the solubility of hundreds of abundant cellular proteins.

Dysregulated miRNA biogenesis downstream of cellular stress and ALS‐causing mutations: a new mechanism for ALS

A novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re‐organization of DICER and AGO2 protein interactions with their partners is described, which suggests that DicER and miRNAs affect neuronal integrity and are possible therapeutic targets.