부산대학교 도서관

The hereditary motor neuropathies (HMN) encompass diseases of motor axons and neurons and range from the progressive, length dependent distal hereditary motor neuropathies (dHMN) to the developmental, non-progressive dominant congenital spinal muscular atrophies (DCSMA). In this Thesis I have investigated the pathomechanisms of HMN and undertaken a natural history study of patients with dHMN. In Chapter 2 I investigated the pathomechanism of dHMN due to homozygous mutations in the heat shock protein HSJ1, using primary motor neurons (MNs) from HSJ1 knockout mice. Using live cell confocal imaging I examined mitochondrial axonal transport and ER calcium levels, but found no evidence of axonal transport deficits or ER stress. In Chapter 3 I examined the pathomechanism of dHMN due to a novel mutation in FBXO38. FBXO38 modulates the transcriptional activity of KLF7; a transcription factor with a role in neuronal development and repair. I therefore examined neurite outgrowth in lentivirus-infected primary MNs and demonstrated a reduction in neurite outgrowth in mutant FBXO38 infected MNs. In Chapter 4, I identified a mutation in a new disease gene, BICD2, in a family with a form of DCSMA termed lower extremity dominant SMA. BICD2 is a dynein adaptor protein and using immunoprecipitation I found that two disease mutations in BICD2 increase dynein binding affinity. In Chapter 5, I performed a genetic study of the HMNs and showed that mutations in HSPB1 are the most common cause of dHMN. I also evaluated plasma neurofilament heavy chain (NFH) as a biomarker of disease activity in the inherited neuropathies but was unable to detect a difference between patients and healthy volunteers. This would suggest that plasma NFH levels are not a suitable biomarker of disease activity in the inherited neuropathies.