Mustill, W.; (2010) The role of the molecular chaperone HSJ1 in amyotrophic lateral sclerosis. Doctoral thesis, UCL (University College London).
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective death of motor neurons. Mutations in the SOD1 gene lead to protein misfolding and cause a dominant familial form of ALS (fALS). The accumulation of misfolded proteins in proteinaceous inclusions is a prominent pathological feature in ALS and other related neurological diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. The degradation of misfolded proteins by the proteasome involves the cooperation of molecular chaperones and ubiquitin chain recognition factors. The molecular chaperone Homo sapiens DnaJ 1(HSJ1) combines the ability to bind misfolded proteins with a J domain that stimulates substrate loading onto heat shock protein 70 (Hsp70) and ubiquitin interaction motifs to bind ubiquitylated chaperone clients, and has previously been shown to protect neurons against polyglutamine mediated protein aggregation. Therefore, the effect of HSJ1 on mutant SOD1 misfolding and aggregation was studied in vitro and in vivo. An in vitro model of SOD1 aggregation was developed and showed that the accumulation of mutant SOD1 inclusions was ameliorated in the presence of HSJ1a or HSJ1b. To test if this anti-aggregation effect of HSJ1 was capable of protecting motor neurons in vivo, a panel of HSJ1 transgenic mice were crossed with G93A SOD1 mutant mice. SOD1 mutant mice over expressing human HSJ1a had a significantly greater number of surviving motor units than control mutant SOD1 mice at a late stage of disease progression. In contrast, SOD1 mice over-expressing HSJ1b were not found to differ in motor unit number from control SOD1 mice. HSJ1 knock-out animals were also investigated. Interestingly, HSJ1-/- mice had fewer motor units in the extensor digitorum longus (EDL) muscle than WT mice at 120 days of age and also at 60 days of age (young adults). SOD1 mice with HSJ1 knocked out showed that although at 120 days of age SOD1 HSJ1-/- mice were of a similar strength to SOD1 mice, fewer motor units survived in the EDL muscle. The work presented in this thesis suggests that HSJ1 may be important for the maintenance of motor neurons.
|Title:||The role of the molecular chaperone HSJ1 in amyotrophic lateral sclerosis|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology > Institute of Ophthalmology - Genetics|
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