Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer's and Parkinson's diseases

Abstract

Summary Mitochondrial dysfunction is an important intracellular lesion associated with a wide variety of diseases including neurodegenerative disorders. In addition to aging, oxidative stress and mitochondrial DNA mutations, recent studies have implicated a role for the mitochondrial accumulation of proteins such as plasma membrane associated amyloid precursor protein (APP) and cytosolic alpha synuclein in the pathogenesis of mitochondrial dysfunction in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. Both of these proteins contain cryptic mitochondrial targeting signals, which drive their transport across mitochondria. In general, mitochondrial entry of nuclear coded proteins is assisted by import receptors situated in both outer and inner mitochondrial membranes. A growing number of evidence suggests that APP and alpha synclein interact with import receptors to gain entry into mitochondrial compartment. Additionally, carboxy terminal cleaved product of APP, ∼ 4kDa Abeta, is also transported into mitochondria with the help of mitochondrial outer membrane import receptors. This review focuses on the mitochondrial targeting and accumulation of these two structurally different proteins and the mode of mechanism by which they affect the physiological functions of mitochondria

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…These same doses are neuroprotective in more mature neurons (Lambert et al, 1998;Van Eldik and Wainwright, 2003;Yankner and Lu, 2009). The additive effects from S100B and APP may depend upon their common activation through the extracellular RAGE receptor which has been shown to regulate intracellular mitochondrial function (Devi and Anandatheerthavarada, 2010;Donato, 2003;Leclerc et al, 2010;Manczak et al, 2006). The in vitro observations from DS HNPs are consistent with in vivo observations in polytransgenic mice.…”

“…APP is a membrane protein associated with neuronal survival and overexpression of APP and its products Abeta has been attributed to neurodegeneration in DS and AD (Conti et al, 2010;Isacson et al, 2002;Salehi et al, 2006). APP and Abeta are located in mitochondria (Devi and Anandatheerthavarada, 2010;Manczak et al, 2006). Abeta peptides induce mitochondrial dysfunction and oxidative stress in astrocytes leading to cell death in neurons (Abramov et al, 2004).…”

Targeting NMNAT1 to Axons and Synapses Transforms Its Neuroprotective PotencyIn Vivo

“…Since the C-terminal fragment of APP is not reported to be targeted to mitochondria (Devi and Anandatheerthavarada, 2010), it is possible that the striking mitochondria localization of Ax-NMNAT1 is determined by NMNAT1 itself. When ectopically present in axons NMNAT1 may dynamically associate with mitochondria.…”

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

“…Alternatively, HSA21 gene S100B may target mitochondrial proteins such as p53 and ATPase ATAD3A, thereby assisting the cytoplasmic processing of proteins for proper folding and subcellular localization [117][118][119][120][121]. Another HSA21 gene APP and its product beta amyloid can interact with import receptors to gain entry into mitochondrial compartment, where they accumulate and affect the normal function of this pathway [122,123]. Finally, gene expression in mitochondrial oxidative phosphorylation may be modulated by DNA methylation.…”