Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Abstract

SummaryExcessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.

SORLA regulates calpain‐dependent degradation of synapsin

“…Phosphorylation of SORLA in vivo was described before [16][17][18]. Our phosphorylation analysis further detected phosphorylation of synapsin 1 and 2 at the putative 14-3-3 binding sites (Ser666 and Ser546) in mouse cortex, a prerequisite for 14-3-3 binding to these sites (Fig.…”

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…Using SorLA-deficient mice, we have found that in the absence of SorLA, AD pathology is strongly accelerated, suggesting a proximal role of SorLA in AD (18,19) that has led to the current model in which SorLA protects against AD (20).…”

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…Thus, earlier work mainly focused on the neurobiology of these receptors uncovering their ability to sort a number of target proteins in control of neuronal cell death and survival. Neuronal ligands for VPS10P domain receptors include neurotrophins and their receptors, or the amyloid precursor protein and progranulin, etiologic agents in Alzheimer's disease and in frontotemporal lobar degeneration, respectively (reviewed in 2,3 ). However, VPS10P domain receptors are also expressed in peripheral tissues with relevance to cardiovascular and metabolic processes.…”

“…The role of VPS10P domain receptors as causative agents in neurodegenerative diseases has long been appreciated (reviewed in 2,3 ), yet their genetic implication in cardiovascular and metabolic disturbances came as a surprise. Here, we will discuss recent studies that have substantiated the involvement of VPS10P domain receptors in disturbances of the cardiovascular system and the metabolism, including hypercholesterolemia, atherosclerosis, obesity, and diabetes.…”