Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD

NEUROBIOLOGY OF DISEASE

卷:140

Review

Fallini, Claudia^1,2,3  Khalil, Bilal⁴  Smith, Courtney L.⁴  Rossoll, Wilfried⁴ 

[1] Univ Rhode Isl, George & Anne Ryan Inst Neurosci, Kingston, RI 02881 USA

[2] Univ Rhode Isl, Dept Cell & Mol Biol, Kingston, RI 02881 USA

[3] Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA

[4] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

关键词: Nucleocytoplasmic transport;    Amyotrophic lateral sclerosis;    Frontotemporal dementia;    ALS/FTD;   

DOI  :  10.1016/j.nbd.2020.104835

来源: Elsevier

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease. Loss of nuclear pores and nucleoporin aggregation, altered nuclear morphology, and impaired nuclear transport are some of the most prominent features that have been identified using a variety of animal, cellular, and human models of disease. Here, we review the experimental evidence linking nucleocytoplasmic transport defects to the pathogenesis of ALS/FTD and propose a unifying view on how these defects may lead to a vicious cycle that eventually causes neuronal death.