TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells.

Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells.

Internally tagged Vps10p-domain receptors reveal uptake of the neurotrophin BDNF.

The Vps10p-domain (Vps10p-D) receptor family consists of Sortilin, SorLA, SorCS1, SorCS2, and SorCS3. They mediate internalization and intracellular sorting of specific cargo in various cell types, but underlying molecular determinants are incompletely understood. Deciphering the dynamic intracellular itineraries of Vps10p-D receptors is crucial for understanding their role in physiological and cytopathological processes.

The Batten disease protein CLN3 is important for stress granules dynamics and translational activity.

The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved.

Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?

Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life. Here, we summarize emerging links between the most common late life neurodegenerative disease, Alzheimer's disease, and the most common early life neurodegenerative diseases, neuronal ceroid lipofuscinoses. Genetic studies reported an overlap of clinically diagnosed Alzheimer's disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.

TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease.

Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g.

The adaptor protein PICK1 targets the sorting receptor SorLA.

SorLA is a member of the Vps10p-domain (Vps10p-D) receptor family of type-I transmembrane proteins conveying neuronal endosomal sorting. The extracellular/luminal moiety of SorLA has a unique mosaic domain composition and interacts with a large number of different and partially unrelated ligands, including the amyloid precursor protein as well as amyloid-β. Several studies support a strong association of SorLA with sporadic and familial forms of Alzheimer's disease (AD).

Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system.

PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in components of the γ-secretase underlie familial Alzheimer disease. In addition to its proteolytic activity, supplementary, γ-secretase independent, functions in the macroautophagy/autophagy-lysosome system have been proposed.

Neuronal activity regulates alternative exon usage.

Neuronal activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. A large number of genes regulated by different neuronal plasticity inducing pathways have been identified, but altered gene expression levels represent only part of the complexity of the activity-regulated transcriptional program. Alternative splicing, the differential inclusion and exclusion of exonic sequence in mRNA, is an additional mechanism that is thought to define the activity-dependent transcriptome.

CLN3 regulates endosomal function by modulating Rab7A-effector interactions.

Mutations in are a cause of juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease. Clinical manifestations include cognitive regression, progressive loss of vision and motor function, epileptic seizures and a significantly reduced lifespan. CLN3 localizes to endosomes and lysosomes, and has been implicated in intracellular trafficking and autophagy.

Amyloidosis causes downregulation of SorLA, SorCS1 and SorCS3 expression in mice.

Accumulation of β-amyloid peptide (Aβ) is regarded as a primary cause of Alzheimer's disease (AD). Aβ is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aβ production.

SORCS1 and SORCS3 control energy balance and orexigenic peptide production.

SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis.

Trafficking in Alzheimer's Disease: Modulation of APP Transport and Processing by the Transmembrane Proteins LRP1, SorLA, SorCS1c, Sortilin, and Calsyntenin.

The amyloid precursor protein (APP), one key player in Alzheimer's disease (AD), is extensively processed by different proteases. This leads to the generation of diverging fragments including the amyloid β (Aβ) peptide, which accumulates in brains of AD patients. Subcellular trafficking of APP is an important aspect for its proteolytic conversion, since the various secretases which cleave APP are located in different cellular compartments.

Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments.

Neuronal activity-regulated alternative mRNA splicing.

Activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. Numerous genes whose expression is induced by different neuronal plasticity inducing pathways have been identified, but the alteration of gene expression levels represents only part of the complexity of the activity-regulated transcriptional program. Alternative splicing of precursor mRNA is an additional mechanism that modulates the activity-dependent transcriptional signature.

Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo.

Activity-dependent alteration of the transcriptional program is central for shaping neuronal connectivity. Constitutively expressed transcription factors orchestrate the initial response to neuronal stimulation and serve as substrates for second messenger-regulated kinase signalling cascades. The mitogen-activated protein kinase ERK conveys signalling from the synapse to the nucleus but its genetic signature following neuronal activity has not been revealed.

Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis.

Juvenile neuronal ceroid lipofuscinosis, the most common neurodegenerative disease affecting children, is caused by mutations of the CLN3 gene encoding CLN3, a transmembrane protein with so far undefined function. The embryonic expression of the gene has not been studied in detail before. Moreover, the protein CLN3 was mostly localized on the subcellular level to lysosomes but the exclusiveness is still under debate.

SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport.

Processing of amyloid precursor protein (APP) into amyloid-β peptide (Aβ) is crucial for the development of Alzheimer's disease (AD). Because this processing is highly dependent on its intracellular itinerary, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The sorting receptor SorCS1 has been genetically linked to AD, but the underlying molecular mechanisms are poorly understood.

SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia.

Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes.

Spatiotemporal expression analysis of the growth factor receptor SorCS3.

SorCS3 is a member of the Vps10p-D receptor family. These type I transmembrane proteins are regarded as sorting receptors, and some family members modulate signal transduction pathways by acting as co-receptors. SorCS3 binds the nerve growth factor (NGF) and platelet-derived growth factor (PDGF-BB), but the functional implications of these interactions are poorly understood.

Genome-wide profiling of the activity-dependent hippocampal transcriptome.

Activity-dependent gene expression is central for sculpting neuronal connectivity in the brain. Despite the importance for synaptic plasticity, a comprehensive analysis of the temporal changes in the transcriptomic response to neuronal activity is lacking. In a genome wide survey we identified genes that were induced at 1, 4, 8, or 24 hours following neuronal activity in the hippocampus.

Human sorCS1 binds sortilin and hampers its cellular functions.

Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into their mature form by enzymatic cleavage of a short N-terminal propeptide. SorCS1 does not bind its propeptide, but sortilin is able to bind not just its own propeptide, but also that of sorCS1. In the present study we show that the propeptide region of sorCS1 contains two separate sites for binding to sortilin and that only one of these sites is removed from human (as opposed to mouse) sorCS1 during processing.

The Vps10p-domain receptor family.

The family of mammalian type-I transmembrane receptors containing a Vps10p domain contains five members, Sortilin, SorCS1, SorCS2, SorCS3, and SorLA. The common characteristic of these receptors is an N-terminal Vps10p domain, which either represents the only module of the luminal/extracellular moiety or is combined with additional domains. Family members play roles in protein transport and signal transduction.