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Heterozygous mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (<jats:italic>GBA1<\/jats:italic>) have been found in PD patients, and some but not all mutations in other lysosomal enzyme genes, for example, <jats:italic>NPC1<\/jats:italic> and <jats:italic>MCOLN1<\/jats:italic> have been associated with PD. We have examined the behaviour and brain structure of mice carrying a D31N mutation in the sulphamidase (<jats:italic>Sgsh<\/jats:italic>) gene which encodes a lysosomal sulphatase. Female heterozygotes and wildtype mice aged 12\u2010, 15\u2010, 18\u2010 and 21\u2010months of age underwent motor phenotyping and the brain was comprehensively evaluated for disease\u2010associated lesions. Heterozygous mice exhibited impaired performance in the negative geotaxis test when compared with wildtype mice. Whilst the brain of <jats:italic>Sgsh<\/jats:italic> heterozygotes aged up to 21\u2010months did not exhibit any of the gross features of PD, Alzheimer's disease or the neurodegenerative lysosomal storage disorders, for example, loss of striatal dopamine, reduced GBA activity, \u03b1\u2010synuclein\u2010positive inclusions, perturbation of lipid synthesis, or cerebellar Purkinje cell drop\u2010out, we noted discrete structural aberrations in the dendritic tree of cortical pyramidal neurons in 21\u2010month old animals. The overt disease lesions and resultant phenotypic changes previously described in individuals with heterozygous mutations in lysosomal enzyme genes such as glucocerebrosidase may be enzyme dependent. By better understanding why deficiency in, or mutant forms of some but not all lysosomal proteins leads to heightened risk or earlier onset of classical neurodegenerative disorders, novel disease\u2010causing mechanisms may be identified.<\/jats:p>","DOI":"10.1002\/jimd.12359","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T02:12:59Z","timestamp":1610676779000},"page":"763-776","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Is <scp>SGSH<\/scp> heterozygosity a risk factor for early\u2010onset neurodegenerative disease?"],"prefix":"10.1002","volume":"44","author":[{"given":"Meghan L.","family":"Douglass","sequence":"first","affiliation":[{"name":"Childhood Dementia Research Group, Hopwood Centre for Neurobiology, Lifelong Health Theme South Australian Health and Medical Research Institute (SAHMRI)  Adelaide South Australia 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