Angelica Hatfield

Introduction. Amyotrophic Lateral Sclerosis(ALS) is a neurodegenerative disease that progressively affects the nerve cells of the brain and spinal cord.¹ ALS progressively degenerates these motor neurons and leads to the progressive muscle weakness.¹ (ALS) can progress by affecting the ability to speak, eat, move and breathe.¹  In this study, we wanted to assess RNA dysfunction by miscoding of Type II intramolecular chaperone and neurodegeneration in (ALS).Chaperone is a type of protein that helps fold and unfold other proteins in molecular pathways in the body. We wanted to assess HspB8/Hsp22 as a molecular chaperone, its’ association with ALS and other neurodegenerative diseases, common pathways between these diseases, and possible mechanism of treatment. Methods. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. HspB8 inhibited the accumulation of SDS-insoluble Htt43Q. Htt43Q then accumulated in the SDS-soluble fraction. (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases in which both diseases associate of misfolded proteins, TDP-43 or FUS, to mis localize and aggregate. We found a shared pathway of these diseases was failure of the neuronal protein quality control (PQC) system.² The PQC system has two pathways, autophagy or proteasome, Dynein-independent pathway. These pathways help degrade misfolded proteins. Several familial ALS/FTD cases are linked to an expansion of a repeated G4C2 hexanucleotide sequence present in the C9ORF72 gene.² These produce Dipeptide repeats (DPRs), that are mainly processed via autophagy. This system is unable to fully clear their aggregated forms. Results. We found that overexpression of (HSPB8) significantly decreased the accumulation of most DPR insoluble species. We found that spinal bulbar muscular atrophy (SBMA) and (ALS), are associated with PQC system- Proteasome, Dynein-independent pathway. We found that inhibition of autophagy pathway does not increase their aggregation⁴ We also found that enhanced misfolded protein clearance is mediated by the proteasome.³ In addition, we found that aggregation of (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity.⁴ Inhibition of TDP-25 and TDP-35 aggregation may protect against cellular damage. We found that overexpression of HSPB8 in immortalized motor neurons decreased the accumulation of TDP-25 and TDP-35 and that protection against mis localized/truncated TDP-43. ⁴ Conclusion. Thus, we concluded that upregulation of HSPB8 might be a possible approach for enhancing degradation of misfolded proteins through the PQC system and decreasing TDP-43 accumulation in ALS.

1. Homepage – ALS Association. ALSA.org. http://www.alsa.org/. Accessed March 26, 2018.
2. Carra S, Seguin SJ, Lambert H, Landry J. HspB8 Chaperone Activity toward Poly(Q)-containing Proteins Depends on Its Association with Bag3, a Stimulator of Macroautophagy. Journal of Biological Chemistry. 2007;283(3):1437-1444. doi:10.1074/jbc.m706304200.
3. Cristofani R, Crippa V, Rusmini P, et al. Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases. Autophagy. 2017;13(8):1280-1303. doi:10.1080/15548627.2017.1308985.
4. Crippa V, Cicardi ME, Ramesh N, et al. The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity. Human Molecular Genetics. 2016;25(18):3908-3924. doi:10.1093/hmg/ddw232.