Parkinson's Disease Risk and Hyperhomocysteinemia: The Possible Link

Abstract

Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.

Keywords: Degenerative brain disorders; Hyperhomocysteinemia; Parkinson's disease.

Fig. 1

Neuropathology of Parkinson’s disease

Fig. 2

Chemical structure of Homocysteine

Fig. 3

Pathway of Homocysteine: homocysteine, with the assistance of folate and vitamin B12, is converted to methionine and converted to cysteine with the assistance of vitamin B6

Fig. 4

Homocysteine and synaptic dysfunction

Fig. 5

Role of Homocysteine in neurodegeneration and cognitive impairment: homocysteine, through activation of N-Methyl-D-Aspartate (NMDA) receptors, induces Ca⁺² leading to excitotoxicity, astrocyte activation with release inflammatory mediators and activation of matrix metalloproteinase (MMP) with subsequent BBB injury and microvascular inflammation. These changes cause a reduction of cerebral blood flow (CBF) and synaptic dysfunction with the development of neurodegeneration and cognitive impairment. In addition, neurodegeneration induces a reduction in the expression of brain-derived neurotrophic factor (BDNF), microtubule-associated protein 2 (MAP-2), synapse associate protein 97 (SAP-97), postsynaptic density protein 95 (PSD-95) with the development of synaptic loss

Fig. 6

The link between high Homocysteine and the development of PD

Fig. 7

Mechanism of homocysteine role in Parkinson’s disease