Endogenous histidine peptides are physiological antioxidants that prevent oligodendrocyte cell death and myelin loss in vivo.

Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte-selective carns1-KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1-KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes.

Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis.

Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.

Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism.

SIAH proteins regulate the degradation and intra-mitochondrial aggregation of PINK1: Implications for mitochondrial pathology in Parkinson's disease.

Parkinson's disease (PD) is characterized by degeneration of neurons, particularly dopaminergic neurons in the substantia nigra. PD brains show accumulation of α-synuclein in Lewy bodies and accumulation of dysfunctional mitochondria. However, the mechanisms leading to mitochondrial pathology in sporadic PD are poorly understood.

Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?

Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) as well as frontotemporal lobar degeneration (FTLD). The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression.

ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA.

Mitochondrial DNA (mtDNA) encodes several key components of respiratory chain complexes that produce cellular energy through oxidative phosphorylation. mtDNA is vulnerable to damage under various physiological stresses, especially oxidative stress. mtDNA damage leads to mitochondrial dysfunction, and dysfunctional mitochondria can be removed by mitophagy, an essential process in cellular homeostasis.

SUMOylation in α-Synuclein Homeostasis and Pathology.

The accumulation and aggregation of α-synuclein are central to Parkinson's disease (PD), yet the molecular mechanisms responsible for these events are not fully understood. Post-translational modifications of α-synuclein regulate several of its properties, including degradation, interaction with proteins and membranes, aggregation and toxicity. SUMOylation is a post-translational modification involved in various nuclear and extranuclear processes, such as subcellular protein targeting, mitochondrial fission and synaptic plasticity.

Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.

Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson's disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption.

The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose. Astrocytic l-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain d-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of l-and d-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse.

Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson's disease.

This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia.

SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation.

α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation.

AF-6 Protects Against Dopaminergic Dysfunction and Mitochondrial Abnormalities in Models of Parkinson's Disease.

Afadin 6 (AF-6) is an F-actin binding multidomain-containing scaffolding protein that is known for its function in cell-cell adhesion. Interestingly, besides this well documented role, we recently found that AF-6 is a Parkin-interacting protein that augments Parkin/PINK1-mediated mitophagy. Notably, mutations in Parkin and PINK1 are causative of recessively inherited forms of Parkinson's disease (PD) and aberrant mitochondrial homeostasis is thought to underlie PD pathogenesis.

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.

α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice.

The Threshold Theory for Parkinson's Disease.

Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate from neuron to neuron, we now propose the threshold theory for PD based on evidence of parallel degeneration of both central nervous system (CNS) and peripheral nervous system (PNS) in PD. The functional threshold is lower for the emergence of early symptoms before the classical motor symptoms of PD.

The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway.

PTEN-induced putative kinase 1 (PINK1) and parkin are mutated in familial forms of Parkinson's disease and are important in promoting the mitophagy of damaged mitochondria. In this study, we showed that synphilin-1 interacted with PINK1 and was recruited to the mitochondria. Once in the mitochondria, it promoted PINK1-dependent mitophagy, as revealed by Atg5 knockdown experiments and the recruitment of LC3 and Lamp1 to the mitochondria.

Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.

A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2.

Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson's disease models.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomorphic pathology including deposits of aggregated protein and neuronal degeneration. The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully understood. Here, using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic protein that interacts with α-synuclein and has implications in PD pathogenesis.

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.

Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining mitochondrial integrity and suppressing Parkinsonism.

The alanine-serine-cysteine-1 (Asc-1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission.

Asc-1 (SLC7A10) is an amino acid transporter whose deletion causes neurological abnormalities and early postnatal death in mice. Using metabolomics and behavioral and electrophysiological methods, we demonstrate that Asc-1 knockout mice display a marked decrease in glycine levels in the brain and spinal cord along with impairment of glycinergic inhibitory transmission, and a hyperekplexia-like phenotype that is rescued by replenishing brain glycine. Asc-1 works as a glycine and L-serine transporter, and its transport activity is required for the subsequent conversion of L-serine into glycine in vivo.

Site-specific differences in proteasome-dependent degradation of monoubiquitinated α-synuclein.

The formation of toxic aggregates composed largely of the protein α-synuclein are a hallmark of Parkinson's disease. Evidence from both early-onset forms of the disease in humans and animal models has shown that the progression of the disease is correlated with the expression levels of α-synuclein, suggesting that cellular mechanisms that degrade excess α-synuclein are key. We and others have shown that monoubiquitinated α-synuclein can be degraded by the 26S proteasome; however, the contributions of each of the nine known individual monoubiquitination sites were unknown.

α-Synuclein ubiquitination and novel therapeutic targets for Parkinson's disease.

Accumulation of α-synuclein is key to the pathogenesis of Parkinson's disease (PD), though the exact mechanisms involved in its toxicity are still subject to debate. Increased α-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of α-synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes.

AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease.

Parkin E3 ubiquitin-ligase activity and its role in mitochondria homeostasis are thought to play a role in Parkinson's disease (PD). We now report that AF-6 is a novel parkin interacting protein that modulates parkin ubiquitin-ligase activity and mitochondrial roles. Parkin interacts with the AF-6 PDZ region through its C-terminus.