Author(s): Vijay K Ramanan aff1 aff2 aff3 aff4 , Andrew J Saykin aff1 aff2 aff3 aff4
Alzheimer's disease; apoptosis; cognitive aging; drug target; FASTKD2 ; fas-associated serine/threonine kinase domains 2; functional genomics; inflammation; memory; microRNA; mitochondria
Impairment in episodic memory is typically the earliest clinical deficit to appear in Alzheimer's disease (AD), the most common cause of dementia and a source of immense personal and societal burden. Unfortunately, the mechanisms underlying AD and other age-related conditions causing cognitive deficits are only partially understood, limiting the development of disease-modifying therapies and novel early diagnostic biomarkers.
Recently, we reported the discovery of a SNP in the FASTKD2 gene associated with better memory performance in a large sample of older Americans [1 ]. We also demonstrated that this new memory-protective SNP was associated with increased volume and gray matter density in the hippocampus, a key brain structure for encoding and retrieving memories that is among the earliest regions affected by AD. Shortly thereafter, a separate report from an independent group identified perturbations in FASTKD2 expression in brain astrocytes derived from postmortem tissue samples from AD patients [2 ].
Prior to these studies, FASTKD2 had not been linked to cognition or AD. This new evidence obtained through diverse methodologies and analytical strategies suggests that FASTKD2 may have potential as a novel target for biomarker and drug development against AD and age-associated cognitive decline. As a result, this is an opportune moment to critically appraise extant knowledge about FASTKD2 and its functional pathways in order to guide next steps aimed at translating mechanistic knowledge into potential clinical strategies.
FASTKD protein family
FASTKD2 encodes one of a family of proteins (including FASTK and FASTKD1-5) that share a common structure including a mitochondrial targeting domain, multiple serine/threonine kinase domains and an RNA-binding domain [3 ]. Much of the early literature on this protein family focuses on FASTK, which constitutively inhibits apoptosis when tethered to the outer mitochondrial membrane but promotes apoptosis when released to the cell cytoplasm following activation of the Fas/CD95 'death receptor' [ 3,4 ]. The proapoptotic function of FASTK is mediated by its binding and modulating the function of TIA1, an mRNA-binding protein that normally silences the production of apoptotic and inflammatory mediators including TNF-[alpha] [5 ].
As discussed below, initial studies of the other FASTKD protein family members indicate broadly shared functions with FASTK. This evidence is not surprising given the common structure and mitochondrial localization of these proteins. However, a closer examination of these putative functional pathways can provide mechanistic clues to characterize the particular impact of FASTKD2 on brain structure and function (Supplementary Figure 1; see online at: www.futuremedicine.com/doi/suppl/10.2217/pgs.15.8).
FASTKD2 & apoptosis
The first functional study of FASTKD2 ensued following the discovery of gene mutations causing a rare mitochondrial encephalomyopathy [6 ]. Due to its FASTK domain, the authors hypothesized a role for the FASTKD2 protein in apoptosis and found that on treatment with staurosporine (a well-described inducer of apoptosis), cells with loss-of-function FASTKD2 mutations exhibited less apoptosis while cells with FASTKD2 overexpression...