Date Published: June 1, 2018
Publisher: JKL International LLC
Author(s): Ting Shen, Yuyi You, Chitra Joseph, Mehdi Mirzaei, Alexander Klistorner, Stuart L. Graham, Vivek Gupta.
Brain-derived neurotrophic factor (BDNF) has a unique role in the neuronal development, differentiation, and survival in the developing and adult nervous system. A common single-nucleotide polymorphism in the pro-region of the human BDNF gene, resulting in a valine to methionine substitution (Val66Met), has been associated with the susceptibility, incidence, and clinical features of several neurodegenerative disorders. Much research has been dedicated to evaluating the effects of polymorphism in the past decade, and functional effects of this genetic variation. A better understanding of how this naturally occurring polymorphism associates with or influences physiology, anatomy, and cognition in both healthy and diseased adults in neurodegenerative conditions will help understand neurochemical mechanisms and definable clinical outcomes in humans. Here we review the role and relevance of the BDNF Val66Met polymorphism in neurodegenerative diseases, with particular emphasis on glaucoma, multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Several controversies and unresolved issues, including small effect sizes, possible ethnicity, gender, and age effects of the BDNF Val66Met are also discussed with respect to future research.
The neurotrophin family consists of four major types of structurally related proteins with similar function, namely the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). The neurotrophins have similar molecular weights (13.2-15.9 kDa), isoelectric points (within the range of 9-10), and share approximately 50% of the identity in primary structure [3, 4]. Among these neurotrophins, BDNF has emerged as a major regulator for several types of neurons, including sensory neurons, retinal ganglion cells, spinal motor neurons, certain cholinergic neurons, and some dopaminergic neurons . It has been reported that some BDNF precursor (pro-BDNF) is released extracellularly and mediates tropomyosin receptor kinase B (TrkB) receptor phosphorylation . The synthesis of BDNF is influenced by neuronal activity in the brain and plays a unique role in synaptic transmission and plasticity. BDNF is widely expressed in the CNS, and its expression is decreased in several neurodegenerative diseases as demonstrated by post-mortem studies, including in AD [7-9], PD , and Huntington’s disease (HD) . It has also been demonstrated that BDNF concentration is reduced in individuals with major depression and increases after antidepressant drug treatment .
The BDNF gene is localized on chromosome 11 band p13  and comprises 11 exons and 9 functional promoters . It can produce at least 34 mRNA transcripts responding to a variety of stimuli .
Since neurotrophins are essential for neuronal function, development, survival and regeneration, gene variations encoding these proteins can confer susceptibility to neurodegenerative disorders .
Alzheimer disease (AD) is an irreversible neurodegenerative disorder associated with specific pathological changes leading to neurodegeneration and progressive symptoms of dementia. AD is clinically characterized by memory impairment, loss of cognitive functions and behavioural impairment, and pathologically by the presence of beta amyloid (Aβ) andhyperphosphorylated Tau protein plaques along with neurofibrillary tangles in the brain . It has been estimated that 26.6 million people worldwide were afflicted with AD in 2006, and the global prevalence is expected to quadruple to approximately 106 million by the year of 2050 . Despite major efforts in research and drug development, no effective treatments or drugs have been developed to prevent AD progression .
Parkinson’s disease is a progressive neurodegenerative disease featured by the death of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies . Like other neurodegenerative disorders showing non-mendelian inheritance, the pathogenesis of PD remains unclear, however several studies implicate a complex interplay between genetic and environmental impacts in the causation of PD .
Neurodegenerative disorders bring about major socioeconomic burden for patients and society. Therefore, it is of great interest to understand the cellular and molecular pathological basis responsible, as there are currently no effective available therapeutic strategies to reverse or halt the degenerative process. In this review article, we discuss the potential involvement of BDNF polymorphism in several neurodegenerative disorders, and conclude that the evidence is mixed in terms of implicating the SNP in several common diseases. To answer the question, prospective cohort studies, especially with longitudinal assessments of the progression of neurodegenerative disorders, are needed. Its role in glaucoma has not been studied in depth, and since BDNF is critical to ganglion cell survival, there is the potential that the SNP may be a factor in certain subtypes of glaucoma.