New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

Abstract

Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no “one size fits all” therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential.

Identification and verification of genes associated with hypoxia microenvironment in Alzheimer's disease

“…For example, certain genetic variations, such as single nucleotide polymorphisms (SNPs), in the BDNF gene have been linked to an increased risk of developing conditions like Alzheimer's disease, depression, schizophrenia, and bipolar disorder. 38,39 These variations may impact BDNF expression or protein function, leading to disrupted neurodevelopment or impaired synaptic plasticity. In uenced by the BDNF locus in chromosome 11, the circulating BDNF level participates in the severity of AD 40 .…”

Combined Associations of Genetic and Environmental Risk Factors in Age of Parkinson’s Disease Onset

“…Physical activity can modify synaptic connectivity within the dopamine (DA)depleted striatum 35 , directly increasing stimulus-evoked DA release or decreasing DA decay, which improves behavioral outcomes in rodent neurotoxicant-induced models 36,37 . In addition, physical activity has been shown to suppress oxidative stress and promote the expression of neurotrophic factors 38 , thereby potentially attenuating dopaminergic neuron degeneration and contributing to the neuroplasticity and survival of dopaminergic neurons 39,40 . In contrast, EDS is thought to be a potential prodromal symptom of PD with similar neuropathological lesions.…”

In silico analysis of the Val66Met mutation in BDNF protein: implications for psychological stress

“…Sortilin interacts with proBDNF and controls the activity-dependent release of BDNF in cortical neurons, processing and transporting BDNF into neurons (Ho et al 2019 ). However, it has been discovered that sortilin truncation mutations disrupt the sorting of BDNF to particular vesicles, impairing its appropriate transport and release (Szarowicz et al 2022 ). One of the several circumstances that can lead to the disruption of the sortilin-BDNF interaction is the presence of Met alteration in the prodomain area of BDNF, which has been shown to decrease sortilin's ability to bind to BDNF.…”