Transcription factors from multiple families ensure enhancer selectivity and robust neuron terminal differentiation

SUMMARYTo search for general principles underlying neuronal regulatory programs we built an RNA interference library against all transcription factors (TFs) encoded in C. elegans genome and systematically screened for specification defects in ten different neuron types of the monoaminergic (MA) superclass.We identified over 90 TFs involved in MA specification, with at least ten different TFs controlling differentiation of each individual neuron type. These TFs belong predominantly to five TF families (HD, bHLH, ZF, bZIP and NHR). Next, focusing on the complexity of terminal differentiation, we identified and functionally characterized the dopaminergic terminal regulatory program. We found that seven TFs from four different families act in a TF collective to provide genetic robustness and to impose a specific gene regulatory signature enriched in the regulatory regions of dopamine effector genes. Our results provide new insights on neuron-type regulatory programs that could help better understand specification and evolution of neuron types.

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice

Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.

Clinical Differentiation of Essential Tremor and Parkinson's Disease

We present clinical features and tremor characterization in a patient with Parkinson's disease (PD) as well as in two cases of essential tremor (ET) with some parkinsonian features but no evidence of dopaminergic terminal loss on 123I-FP-CIT Single Photon Emission Computed Tomography (SPECT). Relatively slow frequency rest tremor and bilateral upper extremity bradykinesia without decrementing amplitude were observed in the ET cases, with unilaterally decreased arm swing in case 3. Alternating rest tremor and re-emergent tremor with 13 second latency was confirmed in the PD case. Re-emergent tremor had alternating characteristics, which to our knowledge has not been previously reported. The ET cases had synchronous postural tremor. Alternating re-emergent tremor in PD provides further evidence for re-emergent tremor as an analogue of rest tremor in PD. Two cases of ET with synchronous postural tremor and one to two year history of parkinsonian features had no evidence of dopaminergic terminal loss up to 40 years after the initial onset of ET. Tremor synchronicity characterization can assist in differential diagnosis between the two disorders.