Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-␤ (A␤) peptides, which are derive from processing of the ␤-amyloid precursor protein (APP), better named amyloid-␤ precursor protein (A␤PP), by secretases. The A␤PP intracellular domain (AID), which is released together with A␤, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A␤PP processing are poorly understood. As cleavage of other ␥-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A␤PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A␤PP. Interestingly, 17 amino acids corresponding to the NH 2 -terminal portion of A␤ are necessary for this interaction. Moreover, BRI2 expression regulates A␤PP processing resulting in reduced A␤ and AID levels. Altogether, these findings characterize the BRI2-A␤PP interaction as a regulatory mechanism of A␤PP processing that inhibits A␤ production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A␤PP processing would define dysregulation of A␤PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD. A␤PP1 is an ubiquitous type I transmembrane protein (1, 2) that undergoes a series of endoproteolytic events (3-5). A␤PP is first cleaved at the plasma membrane or in intracellular organelles by ␤-secretase (6). While the ectodomain is released extracellularly (sAPP␤) or into the lumen of intracellular compartments, the COOH-terminal fragment of 99 amino acids (C99) remains membrane bound. In a second, intramembranous proteolytic event, C99 is cleaved, with somewhat lax site specificity, by the ␥-secretase. Two peptides are released in a 1:1 stoichiometric ratio: the amyloidogenic A␤ peptide, consisting of 2 major species of 40 and 42 amino acids (A␤40 and A␤42, respectively), and an intracellular product named AID or AICD, which is very short-lived and has been identified only recently (7-9). In an alternative, nonamyloidogenic proteolytic pathway, A␤PP is first processed by ␣-secretase in the A␤ sequence leading to the production of the sAPP␣ ectodomain and the membrane-bound COOH-terminal fragment of 83 amino acids (C83). C83 is also cleaved by the ␥-secretase into the P3 and AID peptides. While A␤ is implicated in the pathogenesis of Alzheimer disease, AID mediates most of the A␤PP signaling functions. A pathogenic role for A␤PP processing in AD has been ascertained by the finding that mutations in presenilins (10 -13), key components of the ␥-secretase, and A␤PP (14) cause autosomal dominant familial forms of AD. Thus, because of its biological and pathological import...

Genetic alterations of amyloid

Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.

BackgroundSpinocerebellar ataxia (SCA) is a genetically heterogeneous disease. To date, 36 dominantly inherited loci have been reported, and 31 causative genes have been identified.ResultsIn this study, we analyzed a Japanese family with autosomal dominant SCA using linkage analysis and exome sequencing, and identified CACNA1G, which encodes the calcium channel CaV3.1, as a new causative gene. The same mutation was also found in another family with SCA. Although most patients exhibited the pure form of cerebellar ataxia, two patients showed prominent resting tremor in addition to ataxia. CaV3.1 is classified as a low-threshold voltage-dependent calcium channel (T-type) and is expressed abundantly in the central nervous system, including the cerebellum. The mutation p.Arg1715His, identified in this study, was found to be located at S4 of repeat IV, the voltage sensor of the CaV3.1. Electrophysiological analyses revealed that the membrane potential dependency of the mutant CaV3.1 transfected into HEK293T cells shifted toward a positive potential. We established induced pluripotent stem cells (iPSCs) from fibroblasts of the patient, and to our knowledge, this is the first report of successful differentiation from the patient-derived iPSCs into Purkinje cells. There was no significant difference in the differentiation status between control- and patient-derived iPSCs.ConclusionsTo date, several channel genes have been reported as causative genes for SCA. Our findings provide important insights into the pathogenesis of SCA as a channelopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0180-4) contains supplementary material, which is available to authorized users.

Proteolytic processing of amyloid ␤ protein precursor (A␤PP) generates peptides that regulate normal cell signaling and are implicated in Alzheimer's disease pathogenesis. A␤PP processing also occurs in nerve processes where A␤PP is transported from the cell body by kinesin-I, a microtubule motor composed of two kinesin heavy chain and two kinesin light chain (Klc) subunits. A␤PP transport is supposedly mediated by the direct A␤PP-Klc1 interaction. Here we demonstrate that the A␤PP-Klc1 interaction is not direct but is mediated by JNK-interacting protein 1 (JIP1). The phosphotyrosine binding domain of JIP1 binds the cytoplasmic tail of A␤PP, whereas the JIP1 C-terminal region interacts with the tetratrico-peptide repeats of Klc1. We also show that JIP1 does not bridge the A␤PP gene family member A␤PP-like protein 2, APLP2, to Klc1. These results support a model where JIP1 mediates the interaction of A␤PP to the motor protein kinesin-I and that this JIP1 function is unique for A␤PP relative to its family member APLP2. Our data suggest that kinesin-I-dependent neuronal A␤PP transport, which controls A␤PP processing, may be regulated by JIP1.Alzheimer's disease is characterized by the deposition of A␤ peptides, which are cleaved off from A␤PP 1 (1, 2). A␤PP is transported along axons via conventional kinesin-I-dependent fast anterograde transport (3, 4), which might be involved in processing of A␤PP (5). It has been proposed that the kinesindependent transport of A␤PP is mediated by the direct binding of A␤PP to the TPR domain of Klc (4).The TPR domain of Klc has been shown to bind JIP proteins (6). The JIP protein family, members of which were initially isolated as scaffolds for kinases of the JNK cascade, consists of three proteins: JIP1 (7), JNK-interacting protein 2 (JIP2) (8), and JSAP1/Sunday Driver/JNK-interacting protein 3 (JIP3) (9 -11). JIP1 has two alternatively spliced forms in mouse, JIP1a, and JIP1b. JIP1b (referred to as JIP1 in this manuscript) and JIP2, which are conserved between human and mouse, contain a C-terminal Src homology region 3 and a PTB domain. JIP1a, which has not been found in humans, lacks a complete PTB domain. JIP3 is structurally unrelated (11). Of interest, JIP1 has also been identified in yeast two-hybrid screenings performed to isolate A␤PP-interacting proteins. The PTB domain of JIP1 binds to the YENPTY motif found in the A␤PP intracellular domain (AICD/AID) (12, 13). The biological relevance of the JIP1-A␤PP interaction is underlined by the evidence that these two proteins interact in mouse brain (13).The direct binding of Klc to AID has been a puzzle to us because Klc has never been cloned as an AID-interacting protein, despite extensive yeast two-hybrid screenings performed in many laboratories, including ours. On the contrary, Klc1 was one of the predominant proteins isolated in yeast two-hybrid screening using the C terminus of JIP1 as bait (data not shown). This apparent paradox can be resolved by postulating that the interaction between Klc and A␤PP is indirect and tha...