Faculty Bibliography

In this article in the legend for figure 2 the text "6 ≥ 1 in at least one data point (BL to Y3); pRBD−: subjects with RBDSQ question 6 = 0 at all data points (BL to Y3); DysA+: subject with SCOPA-AUTscore ≥7 in at least one data point (BL to Y3); DysA−: subjects with SCOPA-AUT" should have read "6 ≥ 1 at BL; pRBD−: subjects with RBDSQ question 6 = 0 at BL; DysA+: subject with SCOPA-AUT score ≥7 at BL; DysA−: subjects with SCOPA-AUT < 7 at BL." The original article has been corrected.

Non-motor symptoms of Parkinson's disease (PD) such as dysautonomia and REM sleep behavior disorder (RBD) are recognized to be important prodromal symptoms that may also indicate clinical subtypes of PD with different pathogenesis. Unbiased clustering analyses showed that subjects with dysautonomia and RBD symptoms, as well as early cognitive dysfunction, have faster progression of the disease. Through analysis of the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we tested the hypothesis that symptoms of dysautonomia and RBD, which are readily assessed by standard questionnaires in an ambulatory care setting, may help to independently prognosticate disease progression. Although these two symptoms associate closely, dysautonomia symptoms predict severe progression of motor and non-motor symptoms better than RBD symptoms across the 3-year follow-up period. Autonomic system involvement has not received as much attention and may be important to consider for stratification of subjects for clinical trials and for counseling patients.

PURPOSE OF REVIEW/OBJECTIVE:This article describes and discusses new potential disease-modifying therapies for Huntington's disease that are currently in human clinical trials as well as promising new therapies in preclinical development. RECENT FINDINGS/RESULTS:Multiple potential disease-modifying therapeutics for HD are in active development, including direct DNA/gene therapies, RNA modulation, and therapies targeted at aberrant downstream pathways. The etiology of Huntington's disease (HD) is well-known as an abnormally expanded trinucleotide repeat within the huntingtin gene. However, the pathogenesis downstream of the mutant huntingtin gene is complex, involving multiple toxic pathways, including abnormal protein fragmentation and neuroinflammation. The current treatment of HD focuses largely on symptomatic management. This article discusses new, potential disease-modifying therapies that are currently in human clinical trials and preclinical development.

Objective: To determine whether newly diagnosed Parkinson's disease (PD) patients with REM sleep behavior disorder (RBD) are more likely to have symptoms of autonomic dysfunction.
Background(s): RBD is highly associated with development of asynucleinopathies but only 51% of PD patients have RBD1,2. We addressed whether PD with and without RBD have different clinical phenotypes and progression.
Method(s): Hypothesis driven analysis of 295 early stage PD patients within 2 years from diagnosis on no PD medications from the Parkinson's Progressive Marker Initiative (PPMI) cohort were obtained. Genetic, SWEED and prodromal subgroups were excluded from analysis. RBDSQ equal or greater than 1 for item 6 (q6) was used to identify patients with RBD as this cutoff has greater sensitivity and specificity for identifying true RBD in PD3,4 Results: Subjects from baseline visit were divided in RBD+ (RBDSQ q6>1, n=128) and RBD- (RBDSQ q6<1, n=167). We considered SCOPA subscores (gastrointestinal(GI), urinary(UR), thermoregulation(THERM), cardiovascular(CV), pupillomotor(PM), sex(SEX)), sense of smell (UPSIT), anxiety (STAIT-trait), depression (GDS), motor (updrs-part3) and cognitive function (MOCA), UPDRS total score. Shapiro-Wilk and Mann-Whitney test for non-parametric data were used for the analyses. SCOPA sub-scores for the majority of the autonomic symptoms (GI, THERM, CV, PM) but not UR and SEX, were significantly higher in the REM+ cohort (p=<0.005). The other traits did not show statistically significant differences. Statistical significance between the two groups for GI, THERM, CV remained consistent using other thresholds for differentiating REM+ vs REM- groups (RBDSQ total score greater than 5 or combined RBDSQ total score and q6).
Conclusion(s): Our hypothesis driven analyses show that early stage PD patients with RBD have greater prevalence of autonomic symptoms, without worse UPDRS motor scores. This suggests that brainstem and peripheral autonomic symptoms cluster together, but are not associated with more diffuse involvement of motor systems and cognitive impairment at this early stage of PD. Prior analyses of PPMI data have identified a "diffuse/ malignant" subtype associated with higher UPDRS motor score, RBDSQ score, autonomic symptoms (SCOPA-AUT) and worse cognitive impairment5.6. These differences might be accounted by our more stringent criteria for RBD or our statistical approach using specific hypothesis versus cluster driven analyses

PKMzeta is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMzeta in PKMzeta-null mice. Two hypotheses can account for these findings. First, PKMzeta is unimportant for LTP or memory. Second, PKMzeta is essential for late-LTP and long-term memory in wild-type mice, and PKMzeta-null mice recruit compensatory mechanisms. We find that whereas PKMzeta persistently increases in LTP maintenance in wild-type mice, PKCiota/lambda, a gene-product closely related to PKMzeta, persistently increases in LTP maintenance in PKMzeta-null mice. Using a pharmacogenetic approach, we find PKMzeta-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMzeta-null mice without the target mRNA. Conversely, a PKCiota/lambda-antagonist disrupts late-LTP and spatial memory in PKMzeta-null mice but not in wild-type mice. Thus, whereas PKMzeta is essential for wild-type LTP and long-term memory, persistent PKCiota/lambda activation compensates for PKMzeta loss in PKMzeta-null mice.

In mammals, formation of the auditory sensory organ (the organ of Corti) is restricted to a specialized area of the cochlea. However, the molecular mechanisms limiting sensory formation to this discrete region in the ventral cochlear duct are not well understood, nor is it known whether other regions of the cochlea have the competence to form the organ of Corti. Here we identify LMO4, a LIM-domain-only nuclear protein, as a negative regulator of sensory organ formation in the cochlea. Inactivation of Lmo4 in mice leads to an ectopic organ of Corti (eOC) located in the lateral cochlea. The eOC retains the features of the native organ, including inner and outer hair cells, supporting cells, and other nonsensory specialized cell types. However, the eOC shows an orientation opposite to the native organ, such that the eOC appears as a mirror-image duplication to the native organ of Corti. These data demonstrate a novel sensory competent region in the lateral cochlear duct that is regulated by LMO4 and may be amenable to therapeutic manipulation.

The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis.

Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with histone deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.