Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Abstract

sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid ␤-peptide (A␤), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A␤, whereas ablation of sorLA expression in knockout mice results in increased levels of A␤ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A␤ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A␤ production and plaque formation and promote spontaneous AD.endocytic receptors ͉ knockout mouse ͉ neurodegeneration ͉ Vps10p-domain receptors S orting protein-related receptor (sorLA), also known as LR11, is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (1-4). The protein is a member of a family of neuronal receptors that share structural similarity with the vacuolar protein sorting 10 protein (Vps10p), a sorting protein in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (5). Other family members include the proneurotrophin receptor sortilin (6) and the head activator-binding protein in hydra (7). Because sorLA interacts with the family of GGA (Golgi-localizing, ␥-adaptin ear homology domain, ARFinteracting) adaptors that shuttle between the Golgi and endosomes͞lysosomes, the receptor was proposed to act in intracellular protein trafficking (8). The relevance of such sorLAmediated protein transport in neurons is unclear at present. However, expression profiling has demonstrated reduction of sorLA expression in the brain of patients suffering from Alzheimer's disease (AD), suggesting a causal role for the receptor in the pathogenesis of this disease (9).Central to the pathogenesis of AD is the proteolytic processing of a neuronal membrane protein called the amyloid precursor protein (APP). APP follows a complex intracellular trafficking pathway that influences processing to either a soluble fragment sAPP␣ (nonamyloidogenic) or to sAPP␤ and the insoluble amyloid ␤-peptide (A␤), the principal component of senile plaques (10). The rate of A␤ production is considered the major risk factor for onset of AD (10). En route through the secretory pathway to the cell surface, most newly synthesized APP molecules are cleaved into sAPP␣ by ␣-secretase;...

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Like APP, SorLA is a type I transmembrane protein that is expressed in neurons and is a critical participant in the intracellular transport and processing of APP. Through its Vps10-like structural similarity, SorLA binds to the retromer complex and serves as an adaptor protein for the trafficking of APP from endosomes to the TGN [10]. It has been shown that SorLA levels are reduced in affected brain areas in patients with AD [10], and that overexpression of SorLA redistributes APP to the Golgi apparatus thereby reducing the residency and interaction time of APP and BACE1 in the early endosomes.…”

SORLA regulates calpain‐dependent degradation of synapsin

“…Thus, we analyzed lysates of the neuroblastoma cell line SH-SY5Y stably overexpressing SORLA (SY5Y-S) [5].…”

“…Initially, these orphan receptors were recognized by their structural similarity to the vacuolar protein sorting 10 protein (VPS10P), a trafficking receptor in yeast that sorts target proteins between Golgi and endosomal compartments [3]. However, recently, VPS10P domain receptors emerged as central regulators of neuronal viability and function implicated in many diseases of the nervous system including frontotemporal lobar degeneration [4], Alzheimer disease (AD) [5,6], and bipolar disorders [7].…”

“…According to current concepts, SORLA inhibits trafficking of APP into cellular compartments where secretases reside, thereby reducing the extent of proteolytic breakdown of this precursor into neurotoxic amyloid-β peptides. Based on cumulative evidence from studies in cultured cells [5,8,9] in animal models [2,10] and in humans [6], SORLA is now considered a major risk factor for the sporadic form of AD (reviewed in [11]). …”

Unraveling the biological mechanisms in Alzheimer's disease — Lessons from genomics

“…Despite strong evidence of heritability (Bergem et al, 1997;Gatz et al, 2006), genetic mechanisms involved in late onset AD have been much more difficult to elucidate. The disease pathophysiology in these patients is most likely linked to a whole set of susceptibility genes affecting various pathways, as including those involved in Aβ production, such as SORL1, GAB2 or CH25H (Andersen et al, 2005;Zerbinatti et al, 2008), aggregation, such as CST3 or PRNP (Kaeser et al, 2007;Schwarze-Eicker et al, 2005), and clearance, such as ACE (Bertarm and Tanzi, 2009;Sleegers et al, 2010). The role of several other susceptibility genes has also been implicated in other pathophysiological pathways, such as TF, MAPT and GAB2 in oxidative stress (Yamamoto et al, 2002;Ballatore et al, 2007;Nizzari et al, 2007), CHRNB2 in Ach transmission (Oddo et al, 2006), CR1…”