Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.
Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.
How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson’s disease (PD) remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta (SNc) at 3–4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5 weeks old mice, the toxins decreased SNc dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing PD when multiple factors are combined.
Objectives/Hypothesis: Hearing rehabilitation after translabyrinthine resection of a vestibular schwannoma (VS) has largely been based on the transfer of acoustic stimulus to the contralateral ear, typically through a contralateral routing of signal hearing aid or bone-anchored hearing aid (BAHA). Cochlear implant, either as a subsequent surgery or simultaneously, has become a more common treatment option; however, there is still relatively limited data available on its success. The purpose of this study is to evaluate the early outcomes of simultaneous cochlear implantation in patients with sporadic VS undergoing translabyrinthine resection.Study Design: Prospective, nonrandomized study. Methods: A prospective study of nonrandomized patients was completed at a tertiary care neurotology center. Audiologic outcomes, primarily based on AzBIO in quiet and background noise, as well as consonant-nucleus-consonant (CNC) testing of the affected ears were utilized. Tinnitus, dizziness, and spatial hearing questionnaries were also completed. Audiologic outcomes and questionnaires were compared between the pre-and postoperative groups.Results: Ten patients were included in the study with 3 month follow-up data. There was statistically significant improvement in AzBO with +10 and +5 signal to noise ratio and in quiet, as well as in CNC testing (P < .05). There was a significant improvement in Tinnitus Handicap Inventory between the two groups.Conclusions: Simultaneous cochlear implantation is a viable treatment for hearing loss after translabyrinthine approach to VS. These patients have improved hearing in background noise and tinnitus compared to their preoperative state. Further prognostic data are required to determine which patients are the best candidates.
Objective: To assess differences in postoperative pain, opioid usage, and surgical outcomes between cranioplasty using abdominal fat graft (AFG) versus hydroxyapatite cement (HAC) following translabyrinthine surgery. Study Design: Retrospective case control. Setting: Tertiary referral center. Patients: Sixty translabyrinthine procedures were evaluated, including 30 consecutive HAC patients and 30 matched AFG patients. Patients were matched by age, gender, body mass index, and tumor size. Intervention: Cranioplasty using HAC or AFG following translabyrinthine resection of vestibular schwannoma. Main Outcome Measures: Postoperative patient pain ratings, narcotic usage, inpatient length of stay, and complication rates. Results: Patients who underwent HAC cranioplasty had lower postoperative pain scores on several measures ( p < 0.05) and less postoperative narcotic usage (mean difference of 36.7 morphine equivalents, p ¼ 0.0025) when compared to those that underwent AFG closure. HAC cranioplasty patients had shorter average length of hospital stay (2.2 vs 3.4 days, p ¼ 0.0441). Postoperative cerebrospinal fluid leaks (one in HAC group, two in AFG group) and skin reactions in AFG closure patients (n ¼ 1) were infrequent. Conclusion: HAC cranioplasty is a safe technique comparable to AFG closure following translabyrinthine surgery which can decrease postoperative pain, narcotic usage, and hospital length of stay.
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