Wim Mandemakers

The POU Factor Oct-6 and Schwann Cell Differentiation

The POU transcription factor Oct-6, also known as SCIP or Tst-1, has been implicated as a major transcriptional regulator in Schwann cell differentiation. Microscopic and immunochemical analysis of sciatic nerves of Oct-6−/− mice at different stages of postnatal development reveals a delay in Schwann cell differentiation, with a transient arrest at the promyelination stage. Thus, Oct-6 appears to be required for the transition of promyelin cells to myelinating cells. Once these cells progress past this point, Oct-6 is no longer required, and myelination occurs normally.

A distal Schwann cell‐specific enhancer mediates axonal regulation of the Oct‐6 transcription factor during peripheral nerve development and regeneration

The POU domain transcription factor Oct‐6 is a major regulator of Schwann cell differentiation and myelination. During nerve development and regeneration, expression of Oct‐6 is under the control of axonal signals. Identification of the cis‐acting elements necessary for Oct‐6 gene regulation is an important step in deciphering the complex signalling between Schwann cells and axons governing myelination. Here we show that a fragment distal to the Oct‐6 gene, containing two DNase I‐hypersensitive sites, acts as the Oct‐6 Schwann cell‐specific enhancer (SCE). The SCE is sufficient to drive spatially and temporally correct expression, during both normal peripheral nerve development and regeneration. We further demonstrate that a tagged version of Oct‐6, driven by the SCE, rescues the peripheral nerve phenotype of Oct‐6‐deficient mice. Thus, our isolation and characterization of the Oct‐6 SCE provides the first description of a cis‐acting genetic element that responds to converging signalling pathways to drive myelination in the peripheral nervous system.

DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair‐bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early‐onset Parkinsons disease (PD).

The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals

Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinsons disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock‐in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2‐binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell‐derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic‐specific autophagy defects to Parkinsons disease.

Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice.

miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared to their wildtype littermates. In addition, a decreased number of parallel fibers form synapses on the Purkinje cells. We identified several mRNAs significantly up-regulated in the absence of the miR-29a/b-1 cluster. At the protein level, however, the voltage-gated potassium channel Kcnc3 (Kv3.3) was significantly up-regulated in the cerebella of the miR-29a/b knockout mice. Dysregulation of KCNC3 expression may contribute to the ataxic phenotype.

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency

ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh‐like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations.

Transcriptional Regulation of the Pou Gene Oct-6 in Schwann Cells

Genetic evidence suggests that the POU transcription factor Oct-6 plays a pivotal role as an intracellular regulator of Schwann cell differentiation. In the absence of Oct-6 function Schwann cells are generated in appropriate numbers and these cells differentiate normally up to the promyelin stage at which they transiently arrest. During peripheral nerve development Oct-6 expression is initiated in Schwann cell precursors and is strongly upregulated in promyelin cells. Oct-6 expression is subsequently extinguished in terminally differentiating Schwann cells. Thus, identification and characterisation of the DNA elements involved in this stage specific regulation may lead us to the signaling cascade and the axon-derived signals that drive Schwann cell differentiation and initiate myelination. Here we present experiments that aim at identifying such regulatory sequences.

TMEM230: How does it fit in the etiology and pathogenesis of Parkinson's disease?

Mutations in the transmembrane protein 230 (TMEM230) gene were recently identified in a large Canadian pedigree and 7 smaller Chinese families, nominating TMEM230 as the third gene causing a Mendelian form of late onset Parkinsons disease (PD) with typical Lewy‐body pathology (after synuclein alpha (SNCA) and leucine rich repeat kinase 2 (LRRK2)). The protein encoded by TMEM230 remains largely uncharacterized, but initial evidence points to roles in the trafficking of recycling vesicles, retromers, and endosomes, suggesting intriguing links to the pathways targeted by other PD‐causing genes. The focus on family‐based studies is gaining new momentum in the next‐generation sequencing era, for the discovery of further, high‐penetrance (medically relevant) genetic variants in PD. However, at this junction, important aspects of the TMEM230 story remain unclear, such as the prevalence of these mutations in the Chinese and other populations of the world, the penetrance of the mutations, and even their mode of inheritance. The first replication studies among Chinese and White PD patients have been largely negative. Furthermore, much more work remains ahead to elucidate the mechanisms by which these mutations might lead to neuronal cell death, alpha‐synuclein pathology, and parkinsonism.

Reply to Letter by Dr. Elsayed and colleagues

rigid AR Parkinson’s disease genes targeted next-generation sequencing panel. A minimal threshold depth of 30 3 was used for variant prioritization. Variants with minor allele frequency of <0.1 were selected. Because of consanguinity, homozygous variants were prioritized. A novel nonsense mutation in DNAJC6 (exon 16: c.2365C>T, p.Gln789*) was found in the patient. Sanger sequencing confirmed that the mutation was homozygous only in the patient and absent or heterozygous in 4 other healthy relatives (Figure). This study further underlines the wide variability of age at onset associated with truncating mutations in DNAJC6 (7–42 years). The core clinical features appear quite similar in JOPD and EOPD linked to DNAJC6. However, our patient showed rapid cognitive deterioration and no resting tremor. Furthermore, the presence of visual hallucinations resembling those observed in diffuse Lewy body disease (OMIM phenotype #127750) extend the clinical phenotype associated with DNAJC6 mutations.

microRNAs in Sporadic Alzheimer’s Disease and Related Dementias

Recent studies have demonstrated that non-coding microRNAs (miRNAs), which function at the posttranscriptional level as a rheostat of the transcriptome and proteome, control a variety of neuronal functions as well as neuronal survival. Studies performed in humans support the idea that changes in miRNA expression profiles or target sequences could significantly contribute to the risk of major neurodegenerative diseases such as Alzheimers disease (AD) and Parkinsons disease (PD). MiRNAs seem to participate directly in the regulation of expression of AD-related genes, including APP and BACE1/β-secretase, which are involved in the neurotoxic Aβ peptide production; the latter accumulates in the brains of AD patients. This observation is interesting, as gene dosage effects of the APP gene can cause genetic AD. In this regard, miRNA research appears to be particularly promising for the understanding of the very frequent and poorly understood sporadic forms of AD and probably other neurological disorders.