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Val66Met
A common SNP in the BDNF gene is rs6265. This point mutation in the coding sequence, a guanine to adenine switch at position 196, results in an amino acid switch: valine to methionine exchange at codon 66, Val66Met, which is in the prodomain of BDNF, ,. Interestingly, Val66Met is a mutation unique to humans,.

The Val66Met mutation results in a reduction of hippocampal tissue and has since been reported in a high number of individuals suffering from 1) learning and memory disorders, 2) psychiatric disorders such as schizophrenia and depression , and 3) neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

While Val66Met continues to be strongly correlated with learning and memory deficits and impairments, the exact mechanism remains largely unknown. The current, supported model implicates BDNF secretion and transport as the main problem,.

In Val/Val homozygotes, the most abundant BDNF transcripts in hippocampal neurons (exons 1, 2, 4, & 6) can be found throughout the cell. For example, knockout studies have shown that exon 1 and 4 are essential for dendrites close to the soma while exons 2 and 6 shape distal dendrites. In Val/Met heterozygotes, however, all 4 transcripts can be found in the cell body, producing small, fat neurons with relatively no protrusions. This indicates that BDNF mRNA is not being transported to the dendrites for transcription, and is thus transcribed in the soma, producing an enlarged cell body with few protrusions. The few dendrites formed are drastically underdeveloped. As expected, Met/Met homozygotes are also affected with similar findings to heterozygotes.

The secretion of BDNF upon induced electrical response, activity-dependent secretion of BDNF, is also affected in Val/Met and Met/ Met individuals. The protein products formed become inhibited and are unable to be transported to the dendrites, adding to the accumulation of BDNF in the soma and its absence from the dendrites. This agrees with earlier theories that the Val66Met is a mutation that affects BDNF transport. The mutation is in the prodomain of the BDNF protein and therefore must be cleaved before it can produce dendritic growth. This intriguing finding lead to the discovery that sortilin, a protein needed for sorting BDNF to the appropriate secretory pathway, attaches specifically in the location where the Val66Met amino acid substitution resides