Expression of LIM domain-binding 3 (LDB3), a striated muscle Z-band alternatively spliced PDZ-motif protein in the nervous system.

LIM domain-binding 3 (LDB3) is a member of the Enigma family of PDZ-LIM proteins. LDB3 has been reported as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mechanosensory actin cytoskeleton remodeling. This study shows that LDB3 is broadly expressed in the central and peripheral nervous system of human and mouse. LDB3 is predominantly expressed in the adult stages compared to early development and at a significantly higher level in the spinal cord than in the brain. As in skeletal muscle and heart, LDB3 is extensively alternatively spliced in the neurons. Three novel splice isoforms were identified suggesting splicing-dependent regulation of LDB3 expression in the nervous system. Expression of LDB3 in the motor cortex, cerebellum, spinal motor neuron, peripheral nerve, and neuromuscular junction in addition to skeletal muscle indicates important roles for this PDZ-LIM family protein in motor planning and execution. Moreover, expression in the hippocampal neurons suggests roles for LDB3 in learning and memory. LDB3 interactors filamin C and myotilin are also expressed in the spinal motor neuron, nerve, and neuromuscular junction, thereby providing the basis for neurogenic manifestations in myopathies associated with mutations in these so-called muscle proteins.

Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation.

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

Bone Mineral Density Among Individuals With Residual Lower Limb Weakness After Polio.

BACKGROUND: Literature indicates that individuals with long-term residual lower extremity (LE) weakness after polio have decreased bone mineral density (BMD) related to muscle weakness. Where weakness is asymmetrical, bone densitometry measured only on the stronger LE may misclassify BMD. OBJECTIVE: To determine (1) whether femoral neck BMD differed from side to side in individuals with asymmetrical LE muscle weakness, and (2) the proportion of individuals at risk for underdiagnosis of low bone density or osteoporosis given unilateral assessment of the femoral neck. DESIGN: Retrospective study. SETTING: Outpatient postpolio center. PARTICIPANTS: Patients >18 years old with complete relevant data. MAIN OUTCOME MEASURES: Bone densitometry T scores, BMD categories based on standard T-score ranges, and side of LE weakness determined by a strength score. RESULTS: Forty-three patients had at least 1 femoral neck T score and bilateral LE strength scores. Fourteen (32.5%) had bone densitometry only on their weaker LE and 14 (32.5%) had bone densitometry only on their stronger LE. Of the 15 patients with bone densitometry done on both femoral necks, T scores (mean [SD]) were lower in the weaker LE (-1.73 [1.09]) than the stronger LE (-0.88 [1.0]) (P = .001). Classification of low bone density or osteoporosis was more frequent based on T scores taken on a weaker LE (48.3% and 24.1%, respectively) than from T scores from a stronger LE (41.4% and 6.9%, respectively). CONCLUSIONS: In this small sample, using strong-limb T scores resulted in fewer individuals categorized as having low bone density or osteoporosis than when weak-limb T scores were used. Underestimating BMD loss may lead to undertreatment and increased risk of morbidity, mortality, and costs associated with femoral neck fractures in this high-fall-risk group. LEVEL OF EVIDENCE: III.

Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.

We recently demonstrated that microRNA-218 (miR-218) is greatly enriched in motor neurons and is released extracellularly in amyotrophic lateral sclerosis model rats. To determine if the released, motor neuron-derived miR-218 may have a functional role in amyotrophic lateral sclerosis, we examined the effect of miR-218 on neighbouring astrocytes. Surprisingly, we found that extracellular, motor neuron-derived miR-218 can be taken up by astrocytes and is sufficient to downregulate an important glutamate transporter in astrocytes [excitatory amino acid transporter 2 (EAAT2)]. The effect of miR-218 on astrocytes extends beyond EAAT2 since miR-218 binding sites are enriched in mRNAs translationally downregulated in amyotrophic lateral sclerosis astrocytes. Inhibiting miR-218 with antisense oligonucleotides in amyotrophic lateral sclerosis model mice mitigates the loss of EAAT2 and other miR-218-mediated changes, providing an important in vivo demonstration of the relevance of microRNA-mediated communication between neurons and astrocytes. These data define a novel mechanism in neurodegeneration whereby microRNAs derived from dying neurons can directly modify the glial phenotype and cause astrocyte dysfunction.