ALS (amyotrophic lateral sclerosis) 5 month update
Disrupted neuronal trafficking in amyotrophic lateral sclerosis
Correctly folded proteins leave the ER at specialized sites called ER exit sites via coat protein complex II-coated vesicles and form tubular-like structures known as the ER-Golgi intermediate compartment and subsequently fuse with the Golgi [6, 145]. COPII-coat-mediated transport between the ER and Golgi is facilitated by Rab1 and Rab2, while trafficking from ERGIC back to the ER is regulated by Rab2 in a COPI-dependent fashion or by Rab6 in a COP-independent manner [18, 68]. In the ERGIC, additional sorting takes place where proteins are either transported further towards the Golgi or are recycled back to the ER [64, 111]. Several lines of experimental evidence suggest that dysregulation of C9ORF72 may impact these different transport routes. FUS causes toxicity in part through the formation of abnormal aggregates in the nucleus and cytoplasm of affected neurons and glial cells in ALS patients with FUS mutations [95, 107].
Most of the reported FUS mutations in ALS are missense mutations affecting its C-terminal NLS. Interestingly, the ALS-associated protein aggregates that form as a result of impaired nucleocytoplasmic trafficking may themselves also interfere with nucleocytoplasmic transport of protein and RNA. Finally, repeat expanded C9ORF72 has been proposed to affect trafficking between the nucleus and cytoplasm in different ways. This would suggest that defects in active nuclear export of TDP-43 and FUS only play a minor role in ALS and helps to understand how these proteins accumulate in the cytoplasm in ALS.Intracellular trafficking defects observed in ALS range from accumulation or mislocalization of cell surface receptors or disturbed ER/Golgi trafficking to perturbations in motor proteins and the cytoskeleton. High-resolution live imaging, humanized culture models, and manipulation strategies such as CRISPR/CAS to perform gene knockout or induce epitope tags to endogenously label proteins of interest should be part of the toolbox to further explore the contribution of trafficking defects in ALS.Many open questions with respect to intracellular trafficking and ALS remain.
Protein aggregation is a pathological hallmark of ALS. TDP-43 aggregates are found in the majority of patients, while several other ALS-associated proteins are prone to aggregate, e.g., SOD1, FUS, and DPRs. Defects in intracellular trafficking are linked in several ways to disturbed protein homeostasis. Second, disrupted protein degradation due to perturbed intracellular trafficking may facilitate aggregate formation and stability. 10.Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. 11.Ayaki T, Ito H, Fukushima H, Inoue T, Kondo T, Ikemoto A et al Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant. 77.Iyer S, Subramanian V, Acharya KR C9orf72, a protein associated with amyotrophic lateral sclerosis is a guanine nucleotide exchange factor. 86.Kim SH, Shanware NP, Bowler MJ, Tibbetts RS Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285:34097-34105. 88.Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M et al Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. 127.Nishimura AL, Mitne-Neto M, Silva HCA, Richieri-Costa A, Middleton S, Cascio D et al A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis
Although reported in early descriptions, overt cognitive symptoms and frank dementia were previously thought to be uncommon symptoms of ALS. Conversely, a few patients with FTD develop ALS.30Lomen-Hoerth C.Anderson T.Miller B.The overlap of amyotrophic lateral sclerosis and fronto-temporal dementia. 2006; 67.: 2070-2072.In further support of overlap between these two diseases, structural abnormalities, and specifically fronto-temporal atrophy, have been identified by voxel-based morphometry MRI in patients with ALS and FTD-ALS. Bilateral atrophy of the motor and premotor cortices can develop,30Lomen-Hoerth C.Anderson T.Miller B.The overlap of amyotrophic lateral sclerosis and fronto-temporal dementia. 2003; 23.: 43-51., 69Sasaki S.Iwata M.Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Novel mutations in TARDBP in patients with familial amyotrophic lateral sclerosis.
The El Escorial criteria,74Brooks BR.El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis. 80ISIS Survey: an international study on the diagnostic process and its implications in amyotrophic lateral sclerosis. 87Daube JR.Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. 88Clinical electrophysiology of the upper and lower motor neuron in amyotrophic lateral sclerosis. 2000; 57.: 109-113., 95Belsh JM.Sciffman PL.The amyotrophic lateral sclerosis patient perspective on misdiagnosis and its reprecussions. Finally, patients might also seek alternative treatments, often with little evidence of benefit for ALS, and at great personal financial cost.146Wasner M.Klier H.Borasio GD.The use of alternative medicine by patients with amyotrophic lateral sclerosis.