**7. Huntington's disease**

*Vitamin D Deficiency*

neurodegeneration [130].

**6. Amyotrophic lateral sclerosis**

study has to be taken into consideration [134].

disruptions but no reduced cognitive performance [138].

D3 deficient mice [139, 140].

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons in the brain and spinal cord resulting in paralysis [129]. It is characterized, similar to the abovementioned vitamin D3-associated diseases, by oxidative stress, inflammation, mitochondrial dysfunction, and

Clinical studies result in inhomogeneous findings about a possible role of vitamin D on ALS. A retrospective study including 57 ALS patients reported neither significant differences in 25(OH)D3/D2 blood levels in comparison to 57 healthy individuals nor an improvement of the recorded clinical, ALS-related variables after oral supplementation of 100,000 IU of vitamin D3/week for 4 weeks and thereafter 25,000 IU every 15 days compared to untreated participants. But as discussed by the authors, potential limitations of this study are its retrospective character and the sample size [131]. Two earlier studies also described an absent relationship between serum 25(OH)D3 levels and prognosis in ALS [132, 133]. A very recent study examined the outcome of supplementation of 50,000, 75,000, and 100,000 IU vitamin D3/month on motor dysfunction and clinical progression of ALS. After 6 months, they reported increased levels of serum 25(OH)D3 from approximately 14 ng/mL at starting point to approximately 40 ng/mL after supplementation of 75,000 and 100,000 IU vitamin D3 monthly, but there were no statistically significant differences in the tested clinical ALS characteristics. As the authors mention, the sample size of 10–12 participants per group as well as the short duration of the follow-up

In contrast to these findings, a study from Karam et al. reported vitamin D level less than 30 ng/mL for 81% of their patients with ALS and additionally improvements in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score after supplementation of 2000 IU vitamin D/day for 9 months in 20 participants [135]. In line, a subsequent study described a neuroprotective role for the biologically active form of vitamin D3 as well as a four-time accelerated decline and reduced expectation of life due to hypovitaminosis D [136]. These variable outcomes strengthen the need of further clinical studies with an adequate sample size to reach statistical power and follow-up period analyzing the effect of vitamin D3 on ALS. A first evidence of a genetic link between vitamin D3 and ALS arises from a study from Török and colleagues describing that a SNP in the *VDR* gene is associated with ALS [137]. Further suggestions of a potential role of the VDR in ALS derived from the finding that VDR-knockout mice have muscular and motor

In contrast to the ambiguous clinical studies, animal trials provide evidences for a positive effect of supplemented vitamin D3 on ALS. Studies from Gianforcaro and colleagues reported beneficial functions of high-dose dietary vitamin D3 supplementation on the paw grip endurance and motor performance of transgenic G93A ALS mouse model while decreased performance of functional outcome in vitamin

In reference to the above itemized similarities in ALS characteristics with other neurodegenerative diseases, it is not remarkable that the molecular mechanisms of which vitamin D3 is suggested to have a beneficial influence on ALS are overlapping. Vitamin D3 could decrease the elevated levels of TNF-α or IL-6 found in ALS patients [141] or influence calcium metabolism by regulating the expression of calcium-binding proteins, known to be impaired in ALS [142]. More detailed information can be found in the publications from Gianforcaro et al. and Long

**134**

et al. [143, 144].

Up to this date, only a few studies are available examining a possible relationship between vitamin D3 and Huntington's disease (HD), a neurodegenerative disorder characterized by impairments in cognition, motor behavior, and psychiatrics. HD is caused on molecular level by an expansion of an autosomal dominantly inherited CAG trinucleotide repeat in the huntingtin (*HTT*) gene which is located on chromosome four in humans. This leads to the expression of a mutant huntingtin protein containing an abnormal long polyglutamine repeat [145]. The number of repeats is associated with the risk of developing HD [146]. A recent clinical review describes the consequences of mutant huntingtin on cellular level, including interferences in transcription and protein homeostasis as well as mitochondrial dysfunction and direct toxicity of the altered protein itself. This leads to a disruption in neuronal function and further cell death and neurodegeneration [147]. To our knowledge, there are no current epidemiological or clinical studies suggesting a relationship between vitamin D status and HD, just an explorative study from Chel and colleagues. They reported a high prevalence of deficient or insufficient serum vitamin D level (<50 nmol/L) in 28 individuals with manifest HD [148]. In line with this, a recent study on HD transgenic mice showed no effect on motor performance but a significantly prolonged lifespan after subcutaneous supplementation of 12,000 IU vitamin D3 per kilogram weight [149]. Further evidences for an influence of vitamin D3 on HD arise from a recent publication of Seuter and colleagues analyzing the epigenome-wide effects of vitamin D in THP-1 human monocytes. They identified 165 physiologically important target genes after supplementation of 1,25-dihydroxyvitamin D3 being one of them the *HTT* gene [150].
