Clearly, as low vitamin D status and its clinical consequences may be secondary to a host of factors, including advanced age, reduced mobility from disease, reverse causation cannot be excluded. Studies investigating the effect of migration and vitamin D supplementation on PD risk are lacking. There is a clear heritable component in PD. Genetic studies have pointed to a possible role of vitamin D in susceptibility to the disease. Polymorphisms in the VDR gene have been shown to associate with PD risk

in American and Korean cohorts, with the former cohort also showing an age of onset effect [138, 139]. The relatively small sample sizes and the inconsistent replication of SNPs in the VDR gene in discovery and validation sets dampen the impact of these findings. GWAS have identified an increasing number of candidate PF-562271 cell line risk genes in PD, several of which have VDR-binding sites closely associated with them raising the possibility that vitamin D may influence their expression. The biological relevance of a subset of these

susceptibility genes with associated VDR binding on brain function has been well delineated with evidence for roles in nigrostriatal dopaminergic neurotransmission, neurogenesis and neurite outgrowth, and neural ectodermal expression (especially within the marginal and subventricular zones) (see Table 2) [140-144]. Amyotrophic lateral sclerosis (ALS) is a progressive FG 4592 neurodegenerative disease affecting both the central and peripheral nervous systems [145]. ALS pathology reveals degeneration of motor neurones and corticospinal tracts, brainstem nuclei, and spinal cord anterior horn cells, with a subset of patients having intracytoplasmic transactive responsive DNA-binding protein inclusions (TDP-43) [146]. Multiple effector pathways are thought to contribute to ALS pathology including neurotrophic factor deficiency, glutamate toxicity, and damage from ROS [54]. Given that many of these effector

pathways are influenced by vitamin D in rodent models, there has been growing interest in the concept that this secosteroid may influence susceptibility to and disease progression in ALS. The epidemiological evidence incriminating vitamin D as a possible risk factor in ALS is sparse. The relatively Forskolin low population prevalence probably contributes but there may be no association. Season of birth observations have been conflicting with a few studies reporting excess births between April and July [147], and others reporting birth excess in between October and December (with a trough between April and July) [148]. A latitude gradient has been suggested, but the results are divergent. An American cohort outlining the geographic distribution of ALS using mortality data demonstrated a north-west to south-east gradient [149], a finding mirrored in a more recent study which found a higher ALS-associated death rate in more northern states [150].