**3. Parkinson's disease**

As one of the most common neurodegenerative diseases, Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the substantia nigra pars compacta and typical Lewy bodies, aggregates of α-synuclein, provoking oxidative stress and further cell death, leading to impairments in cognition and behavior and to dysautonomia [75].

A number of epidemiological studies were able to indicate an association of vitamin D and PD. Several evidences exist that hypovitaminosis D is more frequent in PD patients [76, 77], and a cohort study with a 29-year follow-up reported a decreased risk of PD in individuals with higher vitamin D serum levels [78]. These findings are supported by the outcomes of recent studies describing significantly reduced levels of serum 25(OH)D3, daily vitamin D intake, and sunlight exposure in PD patients [79]. Besides significantly decreased serum 25(OH)D3 levels, also an association of vitamin D at baseline and disease motor severity after 36 months was observed in a recently published prospective observational study [80]. A clinical study found an inverse relationship between serum vitamin D concentrations and disease severity as well as an influence on balance function in PD patients [81]. A current study reported that vitamin D status of PD patients has no influence on nocturnal changes in blood pressure, a marker of cardiac autonomic dysfunction as non-motor symptom in PD [82]. However, the tight link between serum vitamin D concentrations and risk as well as severity of PD is also underlined by a recent systematic review and meta-analysis of Luo et al. [83].

PD is not only caused by environmental factors, for example, the vitamin D status, but also by genetic components. The first monogenetic mutation, which was

**131**

*The Effects of Vitamin D Deficiency on Neurodegenerative Diseases*

found to be associated with early onset familial PD, is located in the *SNCA* gene that encodes the α-synuclein protein [84]. A recent study was able to show an altered expression of *Snca* in brains of vitamin D-deficient mice, underlining a causal relationship between hypovitaminosis and PD [63]. Consistent with several previous publications, this is also supported by two recent studies analyzing SNPs in *VDR* and the vitamin D-binding protein. Besides the functional VDR polymorphism, FokI was reported to be associated with cognitive decline in PD and ApaI with the risk of PD, while vitamin D-binding protein gene was suggested as a risk factor for PD [85, 86]. In line with this, a double-blind, placebo-controlled intervention study from Suzuki and colleagues, including 114 PD patients, was able to reveal that supplementation of 1200 IU vitamin D3/day prevents disease progression in a VDR FokI genotype-dependent manner [87]. Moreover, high-dose supplementation of vitamin D (10,000 IU/day) resulted in significant improved balance measured via sensory organization test in PD patients with an age of 52–66 but not in older

To elucidate the underlying molecular mechanisms by which vitamin D exerts its potential beneficial role, animal and cell culture experiments were performed. Vitamin D3 seems to have a positive influence on synthesis and storage of dopamine in CNS by protecting against dopaminergic toxins such as 6-hydroxydopamine or hydrogen peroxide in rats [89]. This neuroprotective effect could be due to its ability to elevate the expression of the glial cell line-derived neurotrophic factor (GDNF) that influences the dopaminergic nigrostriatal system [90] and due to its antioxidative properties described before. Furthermore vitamin D3 administration was shown to prevent zinc-induced oxidative stress in substantia nigra of rat brain [91]. Oxidative stress and elevated intracellular-free calcium promote the aggregation of α-synuclein synergistically, and a recent study could show that the vitamin D3 analogue calcipotriol is able to induce the expression of calbindin-D28k, thereby inhibiting the calcium-mediated aggregation of α-synuclein in human neuroblas-

Multiple sclerosis (MS) is a multifactorial, chronic disease of the CNS character-

Epidemiological studies indicate that genetic and environmental factors interact and influence the risk of MS, for example, several SNPs or environmental exposures like an infection with Epstein-Barr virus (EBV), vitamin D status, sunlight exposure, or smoking. There is a high prevalence for MS in areas with low sun/ultraviolet sun exposure [93, 94], and this could be explained by vitamin D [95]. A study from Lucas and colleagues revealed that vitamin D and sun exposure are independent risk factors of CNS demyelination [96]. For an overview over environmental factors and MS, we suggest an article from Ebers GC [97]. Genetic predispositions which are associated with MS are found in genes of the immune system. The strongest correlation was found for genes of the major histocompatibility complex (MHC), especially the HLA genotype HLA-DRB1 [98]. Findings from Ramagopalan and colleagues suggest a direct functional link between known environmental risk factors, for example, vitamin D, and established genetic predispositions. The authors described the localization of a vitamin D response element on the promotor region of *HLA-DRB1* and underlined its functional role by the finding that treatment with calcitriol results in an increased expression [99]. Later on this research group could show that mutations in the *CYP27B1* gene, involved in vitamin D3 metabolism, are causative associated with the risk of MS [100]. Moreover, genetic variations

ized by demyelination, inflammation, and neurodegeneration.

*DOI: http://dx.doi.org/10.5772/intechopen.89160*

individuals [88].

toma cells [92].

**4. Multiple sclerosis**

#### *The Effects of Vitamin D Deficiency on Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.89160*

*Vitamin D Deficiency*

hypovitaminosis D [6].

**3. Parkinson's disease**

behavior and to dysautonomia [75].

systematic review and meta-analysis of Luo et al. [83].

interaction of vitamin D with estrogen and insulin signaling to regulate the identified pathways [62]. Consistently, we could show that a deficit of vitamin D causes a dysregulation of numerous genes that are involved in multiple cellular processes like neurogenesis, inflammation, mitochondrial function, oxidative stress, signal transduction, and APP homeostasis in brains of hypovitaminosis D mice [63]. In respect to the impaired APP homeostasis, several studies using primary cortical neurons or human neuroblastoma cell lines were able to show beneficial effects of vitamin D and its analogues on anabolism and catabolism of the neurotoxic Aβ peptide

[64, 65]. In line with these findings, a vitamin D3-enriched diet leads to an increased Aβ clearance in mouse models of AD [66–68]. Consistent with the results of animal studies, Hooshmand et al. could demonstrate an association of increased plasma 25(OH)D3 levels with higher concentrations of CSF Aβ1-42 in 75 patients, reflecting a decreased Aβ1-42 aggregation in human brain parenchyma [69]. In contrast, a recent cross-sectional study failed to find significant associations between plasma vitamin D levels at baseline and Aβ load in different brain regions. But the authors themselves argue that those findings could be explained by an improper timing of measurements or rather no analysis over time or by a hypovitaminosis D-related cognitive decline independent of APP homeostasis [70]. The potential neuroprotective role of vitamin D3 is based on findings that it regulates the transcription of the neurotrophin nerve growth factor, glial-derived nerve factor, and neurotrophin 3 which are important for neuronal survival [71–73]. Furthermore, the expression of the neuroprotective cytokine IL-34 was shown to be increased in dose- and time-dependent manner by calcitriol in neuroblastoma cells [74]. In respect to a relationship between vitamin D and neuronal calcium levels, a review describes a reduced autophagy due to impairments in calcium signaling as a consequence of

As one of the most common neurodegenerative diseases, Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the substantia nigra pars compacta and typical Lewy bodies, aggregates of α-synuclein, provoking oxidative stress and further cell death, leading to impairments in cognition and

A number of epidemiological studies were able to indicate an association of vitamin D and PD. Several evidences exist that hypovitaminosis D is more frequent in PD patients [76, 77], and a cohort study with a 29-year follow-up reported a decreased risk of PD in individuals with higher vitamin D serum levels [78]. These findings are supported by the outcomes of recent studies describing significantly reduced levels of serum 25(OH)D3, daily vitamin D intake, and sunlight exposure in PD patients [79]. Besides significantly decreased serum 25(OH)D3 levels, also an association of vitamin D at baseline and disease motor severity after 36 months was observed in a recently published prospective observational study [80]. A clinical study found an inverse relationship between serum vitamin D concentrations and disease severity as well as an influence on balance function in PD patients [81]. A current study reported that vitamin D status of PD patients has no influence on nocturnal changes in blood pressure, a marker of cardiac autonomic dysfunction as non-motor symptom in PD [82]. However, the tight link between serum vitamin D concentrations and risk as well as severity of PD is also underlined by a recent

PD is not only caused by environmental factors, for example, the vitamin D status, but also by genetic components. The first monogenetic mutation, which was

**130**

found to be associated with early onset familial PD, is located in the *SNCA* gene that encodes the α-synuclein protein [84]. A recent study was able to show an altered expression of *Snca* in brains of vitamin D-deficient mice, underlining a causal relationship between hypovitaminosis and PD [63]. Consistent with several previous publications, this is also supported by two recent studies analyzing SNPs in *VDR* and the vitamin D-binding protein. Besides the functional VDR polymorphism, FokI was reported to be associated with cognitive decline in PD and ApaI with the risk of PD, while vitamin D-binding protein gene was suggested as a risk factor for PD [85, 86]. In line with this, a double-blind, placebo-controlled intervention study from Suzuki and colleagues, including 114 PD patients, was able to reveal that supplementation of 1200 IU vitamin D3/day prevents disease progression in a VDR FokI genotype-dependent manner [87]. Moreover, high-dose supplementation of vitamin D (10,000 IU/day) resulted in significant improved balance measured via sensory organization test in PD patients with an age of 52–66 but not in older individuals [88].

To elucidate the underlying molecular mechanisms by which vitamin D exerts its potential beneficial role, animal and cell culture experiments were performed. Vitamin D3 seems to have a positive influence on synthesis and storage of dopamine in CNS by protecting against dopaminergic toxins such as 6-hydroxydopamine or hydrogen peroxide in rats [89]. This neuroprotective effect could be due to its ability to elevate the expression of the glial cell line-derived neurotrophic factor (GDNF) that influences the dopaminergic nigrostriatal system [90] and due to its antioxidative properties described before. Furthermore vitamin D3 administration was shown to prevent zinc-induced oxidative stress in substantia nigra of rat brain [91]. Oxidative stress and elevated intracellular-free calcium promote the aggregation of α-synuclein synergistically, and a recent study could show that the vitamin D3 analogue calcipotriol is able to induce the expression of calbindin-D28k, thereby inhibiting the calcium-mediated aggregation of α-synuclein in human neuroblastoma cells [92].
