Travis Green
Neurogenetics
Val66Met Polymorphism Impact on Secretion of BDNF & Spinal Cord Plasticity
BDNF (brain-derived neurotrophic factor) is an important protein found all throughout
the body and functions in many molecular processes (Lamy and Boakye 2013). In the human
genome, the BDNF gene can be found on chromosome 11 with a protein length of 247 amino
acids (Witte et al. 2012). The function of the BDNF protein is not yet completely understood;
however, many studies have identified that BDNF is an essential protein necessary for
hippocampal learning and functional regeneration of injured peripheral nerves (Fritsch et al.
2010). A commonly studied missense single-nucleotide polymorphism (SNP) found within the
BDNF gene is the Valine-to-methionine (val66met) substitution at codon 66. Though the
val66met missense SNP changes the nucleotide and protein sequence, the BDNF protein is still
able to function; however, this polymorphism causes a problem in the body’s ability to secrete
BDNF (Witte et al. 2012). Due to this lack of ability to secrete BDNF, val66met carrying
individuals commonly see complications in tissues where BDNF expression is critical.
When considering the genetics of val66met missense SNP, two genotypes are identified
between normal and mutant carriers. A normal functioning individual is homozygous Val/Val;
whereas an individual carrying both the normal and val66met alleles have a heterozygous
genotype Val/Met that is dominantly expressed as Met (Lamy and Boakye 2013). Homozygous
val66met SNP individuals have no influence on the ability to secrete BDNF (Lamy and Boakye
2013). Met carriers are characterized by their decreased activity-dependent BDNF secretion as
compared to normal-functioning Val/Val homozygotes (Lamy and Boakye 2013). The function
of this gene is also reduced in patients suffering from Alzheimer’s and Huntington’s disease,
which is indicative of the phenotypic effects the expression of val66met has on the individuals
containing the SNP (Lamy and Boakye 2013).
The phenotypic effects observed in heterozygous individuals are related to the
individual’s inability to effectively secrete BDNF. Due to BDNF’s critical role in many bodily
functions, affected individuals suffer from a multitude of complications in many different
physiological processes. For example, Met-carrying individuals suffer from altered cortical
morphology, deficient activity-dependent cortical plasticity, lowered motor cortex function
(Fritsch 2010), and diminished cognitive memory and performance. Since BDNF plays a critical
role in the areas of the body where these complications arise, it’s hypothesized that the lack of
BDNF secretion prevents normal physiological function in any individual carrying the val66met
polymorphism.
In many previous studies, electrical stimulation of the spinal cord and brain has resulted
in the increased expression of BDNF in regions where stimulation is applied. These results are
characterizations of homozygous Val/Val individuals. Increased expression of BDNF in isolated
areas aids in the functional recovery of nerve or spinal cord injuries, and has also been
demonstrated to increase cognitive memory and motor cortex function (Fritsch 2010). The
val66met SNP prevents proper secretion of BDNF in the areas where it is physiologically
needed, thus resulting in the Met carriers phenotypic complications. In the study Lamy and
Boakye conducted, it was discovered that electrical stimulation techniques known to increase
BDNF expression are ineffective in heterozygous Met carriers (Lamy and Boakye 2013). This
was demonstrated by the use of anodal transcutaneous spinal direct current stimulation (tsDCS)
in their study. Homozygous Val/Val individuals, when electrically stimulated, demonstrated
elevated levels of BDNF expression in the areas where the electrode was applied (Lamy and
Boakye 2013). However, it should be noted that heterozygous Met carriers were functionally
unaffected by electrical stimulation techniques (Lamy and Boakye 2013). Effectiveness of tsDCS
was determined by the stimulus-response curves of the soleus H reflex before, during, at current
offset and 15 minutes after stimulation. Heterozygous Met carriers demonstrated no statistically
significant changes between pre- and post-Soleus H Reflex testing. The after effect (Soleus H
reflex 15 minutes after stimulation) observed in Val/Val homozygous individuals in Lamy and
Boakye’s study agrees with the current widely viewed results of elevated BDNF expression by
electrical stimulation (Lamy and Boakye 2013). Normal functioning Val/Val homozygotes
benefit after electrical stimulation techniques by up-regulating BDNF expression in isolated
areas even after the probes are no longer applying electrical stimulation. Met heterozygous
carriers not only do not functionally benefit from initial electrical stimulation, but no significant
effect is observed even 15 minutes post-electrical stimulation.
Since Met carriers are functionally deficient in the secretion of BDNF, even when electric
stimulation is applied to facilitate BDNF expression, clinical concern has been expressed for
val66met-affected individuals in the functional regeneration of spinal cord injuries or PNS
injuries. Some techniques, such as transcranial magnetic stimulation, have been shown to assist
in the secretion of BDNF in Met carriers; however, the results of these experiments have not
been able to be replicated (Fritsch 2010). It’s clear to scientists that electrical stimulation and
exercise induces secretion of BDNF in normal functioning Val/Val homozygotes; however, the
molecular and cellular mechanisms as to why electrical stimulation elevates BDNF expression is
not clearly understood. Further investigation of these therapeutic techniques as tools to induce
BDNF is needed in order to better understand the exact molecular function of BDNF by
electrical stimulation and how the body similarly (if similar) expresses BDNF.
Many different electrical stimulatory techniques and exercise paradigms have been
discovered to up-regulated BDNF, but all typical techniques used to do so are not useful in
val66met-affected individuals. Due to the number of complications seen in these val66metaffected individuals, further research is required to better understand the molecular and cellular
details as to why val66met missense SNP completely ignores all typical techniques used for upregulation of BDNF. It’s clear that the val66met missense SNP significantly impacts brain,
spinal cord and PNS plasticity. A good example of BDNF’s impact of CNS and PNS functional
recovery is the study done by Siironen et al. where patients who initially survived aneurysmal
subarachnoid hemorrhaging demonstrated poor functional recovery of their CNS and PNS if they
were heterozygous for val66met SNP, due to their lack of BDNF secretion in the damaged areas
(Siironen et al. 2007). Investigators who plan to address this issue should consider direct BDNF
application to areas lacking plasticity due to val66met SNP to better determine whether
heterozygous Met carrying individuals can utilize BDNF in injury areas given that the protein is
available abundantly and whether or not the issue with this polymorphism is solely due to the
defective secretion of BDNF. Identifying the exact molecular and/or cellular functions of
individuals affected by val66met will better assist in studies aiming to repair genetically
predisposed conditions.
Works Cited
Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, Lu B. Direct
current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for
motor learning. Neuron 66:198-204, 2010.
Lamy, Jean-Charles, Boakye, Maxwell. BDNF Val66Met polymorphism alters
spinal DC stimulation-induced plasticity in humans. J
Neurophysiology. 2013.
Siironen J, Juvela S, Kanarek K, Vilkki J, Hernesniemi J, Lappalainen J. The
Met allele of the BDNF Val66Met polymorphism predicts poor outcome among survivors of
aneurysmal subarachnoid hemorrhage. Stroke 38:2858-2860, 2007.
Witte AV, Kurten J, Jansen S, Schirmacher A, Brand E, Sommer J, Floel A. Interaction of
BDNF and COMT polymorphisms on paired-associative stimulation-induced cortical
plasticity. J Neurosci 32:4553-4561, 2012.