Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose exact causative mechanisms are still under intense investigation. Several lines of evidence suggest that the anatomical and temporal propagation of pathological protein species along the neural axis could be among the main driving mechanisms for the fast and irreversible progression of ALS pathology. Many ALS‐associated proteins form intracellular aggregates as a result of their intrinsic prion‐like properties and/or following impairment of the protein quality control systems. During the disease course, these mutated proteins and aberrant peptides are released in the extracellular milieu as soluble or aggregated forms through a variety of mechanisms. Internalization by recipient cells may seed further aggregation and amplify existing proteostatic imbalances, thus triggering a vicious cycle that propagates pathology in vulnerable cells, such as motor neurons and other susceptible neuronal subtypes. Here, we provide an in‐depth review of ALS pathology with a particular focus on the disease mechanisms of seeding and transmission of the most common ALS‐associated proteins, including SOD1, FUS, TDP‐43, and C9orf72‐linked dipeptide repeats. For each of these proteins, we report historical, biochemical, and pathological evidence of their behaviors in ALS. We further discuss the possibility to harness pathological proteins as biomarkers and reflect on the implications of these findings for future research.

The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

“…Other ALS-related proteins such as SOD1 [ 160 ], FUS [ 145 ], UBQLN2 [ 161 ], and C9ORF72-derived dipeptide repeat (DPR) proteins [ 162 , 163 ], have been found within toxic aggregates which are positive for several proteasome components [ 164 ], while nonmutated forms of TDP-43 , OPTN , and UBQLN2 have been observed in such ubiquitinated inclusions, further aggravating the disrupted cellular homeostasis in ALS. Strikingly, these toxic aggregates can be released and disseminate, amplifying existing proteostatic imbalances, and propagating the pathology in vulnerable cells, such as MNs [ 165 ].…”

Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins

“…In the present study, we investigated the role of EVs in the secretion of TDP-43 and evaluated a possible role of the CASA complex in this process. We considered all EVs, both SVs for which TDP-43 secretion has already been described [6] and LVs. Indeed, despite the fact that plasma-derived LVs from ALS patients contain FL and fragmented TDP-43 [19], their involvement in TDP-43 trafficking is still unknown.…”

“…Two of the shared mechanisms are: (i) the progressive neurodegeneration arising in specific neurons and spreading to a more extended area, and (ii) the abnormal formation and accumulation of intracellular inclusions of misfolded proteins [1][2][3][4]. These two aspects of NDs are directly related, since misfolded proteins can be transmitted from one cell to another, contributing to the spreading of the disease [5][6][7][8][9]. In fact, affected cells can release misfolded proteins both as free proteins or after their incorporation into lipid bilayer-delimited particles, called extracellular vesicles (EVs); these EVs can be uptaken by other cells transporting their cargo to them [9].…”

“…The EVs release of misfolded proteins can be viewed as a protective mechanism for the secreting cell, but it may also negatively affect recipient cells. EVs could assist (or be part of) the intracellular protein quality control (PQC) system in proteostasis surveillance [6,13,14]. PQC system consists of chaperone and co-chaperone proteins, together with the ubiquitin proteasome system (UPS) and autophagy.…”

Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…In ALS/FTD, FUS or TDP-43 mislocalise to the cytoplasm and form aggregates that are most likely toxic, although loss of function from the nucleus may also be the key disease-causing factor. This mislocalisation is instigated by a number of disruptions, including dysfunctions in proteostasis, nucleocytoplasmic shuttling, and the cellular stress response [ 50 , 51 , 52 ]. Upon stress, TDP-43, FUS, and some other ALS-associated RNA-binding proteins separate into stress granules, which may be the first step in the formation of insoluble aggregates [ 53 , 54 ].…”