Thymic and extrathymic Aire-expressing cells in maternal-fetal tolerance.

Healthy pregnancy requires maternal immune tolerance to both fetal and placental tissues which contain a range of self- and non-self-antigens. While many of the components and mechanisms of maternal-fetal tolerance have been investigated in detail and previously and thoroughly reviewed (Erlebacher A. Annu Rev Immunol. 2013;31:387-411), the role of autoimmune regulator (Aire), a critical regulator of central tolerance expressed by medullary thymic epithelial cells (mTECs), has been less explored. Aire is known to facilitate the expression of a range of otherwise tissue-specific antigens (TSAs) in mTECs, and here we highlight recent work showing a role for mTEC-mediated thymic selection in maintaining maternal-fetal tolerance. Recently, however, our group and others have identified additional populations of extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. These hematopoietic antigen-presenting cells possess the ability to induce functional inactivation and/or deletion of cognate T cells, and deletion of maternal eTACs during pregnancy increases T-cell activation in the lymph nodes and lymphocytic infiltration of the uterus, leading to pregnancy complications including intrauterine growth restriction (IUGR) and fetal resorption. In this review, we briefly summarize findings related to essential Aire biology, discuss the known roles of Aire-deficiency related to pregnancy complications and infertility, review the newly discovered role for eTACs in the maintenance of maternal-fetal tolerance-as well as recent work defining eTACs at the single-cell level-and postulate potential mechanisms by which eTACs may regulate this process.

Mitochondrial genome study in blood of maternally inherited ALS cases.

BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer's and Parkinson's diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Thoracic trauma promotes alpha-Synuclein oligomerization in murine Parkinson's disease.

BACKGROUND: Systemic and neuroinflammatory processes play key roles in neurodegenerative diseases such as Parkinson's disease (PD). Physical trauma which induces considerable systemic inflammatory responses, represents an evident environmental factor in aging. However, little is known about the impact of physical trauma, on the immuno-pathophysiology of PD. Especially blunt chest trauma which is associated with a high morbidity and mortality rate in the elderly population, can induce a strong pulmonary and systemic inflammatory reaction. Hence, we sought out to combine a well-established thoracic trauma mouse model with a well-established PD mouse model to characterize the influence of physical trauma to neurodegenerative processes in PD. METHODS: To study the influence of peripheral trauma in a PD mouse model we performed a highly standardized blunt thorax trauma in a well-established PD mouse model and determined the subsequent local and systemic response. RESULTS: We could show that blunt chest trauma leads to a systemic inflammatory response which is quantifiable with increased inflammatory markers in bronchoalveolar fluids (BALF) and plasma regardless of the presence of a PD phenotype. A difference of the local inflammatory response in the brain between the PD group and non-PD group could be detected, as well as an increase in the formation of oligomeric pathological alpha-Synuclein (asyn) suggesting an interplay between peripheral thoracic trauma and asyn pathology in PD. CONCLUSION: Taken together this study provides evidence that physical trauma is associated with increased asyn oligomerization in a PD mouse model underlining the relevance of PD pathogenesis under traumatic settings.

HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease.

The huntingtin-associated protein 40 (HAP40) is an abundant interactor of huntingtin (HTT). In complexes of these proteins, HAP40 tightly binds to HTT in a cleft formed by two larger domains rich in HEAT repeats, and a smaller bridge domain connecting the two. We show that HAP40 steady-state protein levels are directly dependent on HTT (both normal and mutant HTT) and that HAP40 is strongly stabilized by the interaction with HTT resulting in an at least 5-fold increase in HAP40's half-life when bound to HTT. Cellular HAP40 protein levels were reduced in primary fibroblasts and lymphoblasts of Huntington Disease (HD) patients and in brain tissue of a full-length HTT mouse model of HD, concomitant with decreased soluble HTT levels in these cell types. This data and our previous demonstration of coevolution between HTT and HAP40 and evolutionary conservation of their interaction suggest that HAP40 is an obligate interaction partner of HTT. Our observation of reduced HAP40 levels in HD invites further studies, whether HAP40 loss-of-function contributes to the pathophysiology of HD.

ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues.

BACKGROUND: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). METHODS: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations. RESULTS: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations. CONCLUSION: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.

Frequency and Characteristics of Trials Using Medical Writer Support in High-Impact Oncology Journals.

Importance: The practice of using medical writers to communicate scientific information has gained popularity, but it may affect how and what information is communicated. Objective: To assess characteristics of oncology trials that use medical writers and whether there is an association between the use of medical writers and trial success or the primary outcome evaluated. Design, Setting, and Participants: This cross-sectional study included oncology trials testing a tumor-targeting intervention that were published in The Lancet, The Lancet Oncology, JAMA, JAMA Oncology, Journal of Clinical Oncology, and The New England Journal of Medicine between May 1, 2021, and May 1, 2022. Exposures: Assistance of medical writers or no assistance. Main Outcomes and Measures: The main outcomes were the percentage of studies with medical writers, the percentage of trial successes reported with medical writers, the association between trial success and medical writer use, and the association between a primary end point and medical writer use. Results: Among 270 studies, 141 (52.2%) included a medical writer and 129 (47.8%) did not include a medical writer. Of the studies that included a medical writer, 83 (58.9%) were successful. Of the studies that did not include a medical writer, 64 (49.6%) were successful (P = .16 for difference). Studies with medical writers were less likely than studies without medical writers to have the end point of overall survival (15 [10.6%] vs 17 [13.2%]) and disease-free or event-free survival (16 [11.3%] vs 29 [22.5%]), whereas studies with a medical writer were more likely to have the end point of progression-free survival (32 [22.7%] vs 17 [13.2%]). Use of medical writer was associated with the conclusions being presented favorably in all studies (113 [80.1%] vs 89 [69.0%]; odds ratio [OR], 1.81 [95% CI, 1.04-3.19]), but when adjusted for other variables, there was no association (OR, 1.84 [95% CI, 0.92-3.72]). Conclusions and Relevance: In this cross-sectional study, trials using medical writers were more likely to report surrogate end points, such as progression-free survival, and favorable conclusions, but when adjusted for trial phase, randomization, and study funding, there was no association with favorable conclusions. These findings suggest that journals need heightened scrutiny for studies with medical writers and that authorship should be properly acknowledged.

Ex vivo human testes as a practical model to simulate ultrasound-guided testicular cell transplantation for human fertility restoration.

OBJECTIVE: To develop an ex vivo model to practice ultrasound-guided injection of cellular material into human seminiferous tubules to simulate testicular cell transplantation (TCT). DESIGN: Simulated TCT injections were performed in human testes removed during orchiectomy. The rete testis was the target site of injection. Successful retrograde infiltration of injected material into the lumen of the seminiferous tubules was detected using ultrasound and confirmed with histology. SETTING: Single academic surgical center. PATIENT(S): Adult patients undergoing orchiectomy for nononcologic indications. INTERVENTION(S): The testes were injected with sonographic contrast (Optison), methylene blue, and fluorescent-labeled cells. MAIN OUTCOME MEASURE(S): A characteristic streaming pattern of sonographic contrast in the testis was used to define sonographic success, and the presence of methylene blue and fluorescent-labeled cells within the seminiferous tubules confirmed histologic success. RESULT(S): We performed simulated TCT injections in 30 testes obtained from 16 patients undergoing orchiectomy. We were able to achieve sonographic success in 57% of injections and confirmed that sonographic success is correlated with histologic success. CONCLUSION(S): Testicular cell transplantation injections can be practiced using human testes. As there appears to be a learning curve associated with this procedure, developing this infrastructure to practice these skills is critical before implementation in patients.

Extrathymic Aire-expressing cells support maternal-fetal tolerance.

Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire +) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire + cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.

Hospital complications and costs of spinal arteriovenous malformations in the United States from 2002-2014.

BACKGROUND: Spinal arteriovenous malformations (AVMs) are rare disease entities with significant morbidity if untreated. Risk factors of complications, hospitalization and costs-of-care remain in need of characterization. METHODS: Using the National Inpatient Sample years 2002-2014, adult subjects with spinal AVMs who underwent either laminectomy with lesion excision or endovascular embolization were extracted using ICD-9-CM diagnostic code 747.82. Predictors of inpatient complications, hospital length of stay (HLOS), and discharge home were evaluated using multivariable regression. Cost was evaluated using inflation-adjusted healthcare cost [charge*(cost/charge ratio)]. Mean differences (B), odds ratios (OR) and 95% CIs are reported. Significance was assessed at P<0.001. RESULTS: In 2546 weighted admissions, age was 54.4±16.5-years (laminectomy: 70.0%, embolization: 30.0%). Fifteen percent suffered inpatient complications. Cost of hospitalization was $ 41216±38511 and was elevated for subjects with complications ($67571±2636, vs. no complications: $36562±723, P<0.001). Increased costs for categories of complications ranged from $ 16525 (renal/urinary) to $62246 (thromboembolism). In surgical subjects, complications were more costly ($ 69761±2896, vs. no complications: 36520±809, P<0.001). On multivariable analysis, major/extreme disease severity and major/extreme mortality risk were associated with increased complications and HLOS (P<0.001). Elective admissions had shorter HLOS (B=-4.3-days, [-4.8, -3.8], P<0.001) and higher odds of discharge home (OR=2.6 [2.1-3.2], P<0.001). Laminectomy (vs. embolization) was associated with complications (OR=2.6, 95% CI [1.7-3.8], P<0.001), HLOS (B=3.4-days [2.9-4.0], P<0.001), and decreased discharge home (OR=0.3 [0.2-0.4], P<0.001). CONCLUSIONS: In spinal AVMs, high disease severity, non-elective admissions, and surgery are associated with complications, HLOS, and discharge to a non-home facility. Costs are elevated in patients suffering complications. Future studies are warranted.

Basal impulses: findings from the last twenty years on impulsivity and reward pathways using deep brain stimulation.

INTRODUCTION: Deep brain stimulation (DBS) is an important treatment modality for movement disorders. Its role in tasks and processes of higher cortical function continues to increase in importance and relevance. This systematic review investigates the impact of DBS on measures of impulsivity. EVIDENCE ACQUISITION: A total of 45 studies were collated from PubMed (30 prospective, 8 animal, 4 questionnaire-based, and 3 computational models), excluding case reports and review articles. Two areas extensively studied are the subthalamic nucleus (STN) and nucleus accumbens (NAc). EVIDENCE SYNTHESIS: While both are part of the basal ganglia, the STN and NAc have extensive connections to the prefrontal cortex, cingulate cortex, and limbic system. Therefore, understanding cause and treatment of impulsivity requires understanding motor pathways, learning, memory, and emotional processing. DBS of the STN and NAc shell can increase objective measures of impulsivity, as measured by reaction times or reward-based learning, independent from patient insight. The ability for DBS to treat impulse control disorders, and also cause and/or worsen impulsivity in Parkinson's disease, may be explained by the affected closely-related neuroanatomical areas with discrete and sometimes opposing functions. CONCLUSIONS: As newer, more refined DBS technology emerges, large-scale prospective studies specifically aimed at treatment of impulsivity disorders are needed.

Evaluation of SARS-CoV-2 serology assays reveals a range of test performance.

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.

Test performance evaluation of SARS-CoV-2 serological assays.

BACKGROUND: Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data. METHOD: We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies. The specimen set comprised 128 plasma or serum samples from 79 symptomatic SARS-CoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system. RESULTS: Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.7-94.8%. No consistent cross-reactivity was observed. CONCLUSION: Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.

Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice.

Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1 ) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A , which represents a "second hit" that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A/Tbk1+/- mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.

Caveolin1 Identifies a Specific Subpopulation of Cerebral Cortex Callosal Projection Neurons (CPN) Including Dual Projecting Cortical Callosal/Frontal Projection Neurons (CPN/FPN).

The neocortex is composed of many distinct subtypes of neurons that must form precise subtype-specific connections to enable the cortex to perform complex functions. Callosal projection neurons (CPN) are the broad population of commissural neurons that connect the cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We identify in mouse that the lipid-bound scaffolding domain protein Caveolin 1 (CAV1) is specifically expressed by a unique subpopulation of Layer V CPN that maintain dual ipsilateral frontal projections to premotor cortex. CAV1 is expressed by over 80% of these dual projecting callosal/frontal projection neurons (CPN/FPN), with expression peaking early postnatally as axonal and dendritic targets are being reached and refined. CAV1 is localized to the soma and dendrites of CPN/FPN, a unique population of neurons that shares information both between hemispheres and with premotor cortex, suggesting function during postmitotic development and refinement of these neurons, rather than in their specification. Consistent with this, we find that Cav1 function is not necessary for the early specification of CPN/FPN, or for projecting to their dual axonal targets. CPN subtype-specific expression of Cav1 identifies and characterizes a first molecular component that distinguishes this functionally unique projection neuron population, a population that expands in primates, and is prototypical of additional dual and higher-order projection neuron subtypes.

Apolipoprotein E Epsilon 4 Genotype, Mild Traumatic Brain Injury, and the Development of Chronic Traumatic Encephalopathy.

The annual incidence of mild traumatic brain injury (MTBI) is 3.8 million in the USA with 10⁻15% experiencing persistent morbidity beyond one year. Chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by accumulation of hyperphosphorylated tau, can occur with repetitive MTBI. Risk factors for CTE are challenging to identify because injury mechanisms of MTBI are heterogeneous, clinical manifestations and management vary, and CTE is a postmortem diagnosis, making prospective studies difficult. There is growing interest in the genetic influence on head trauma and development of CTE. Apolipoprotein epsilon 4 (APOE-ε4) associates with many neurologic diseases, and consensus on the ε4 allele as a risk factor is lacking. This review investigates the influence of APOE-ε4 on MTBI and CTE. A comprehensive PubMed literature search (1966 to 12 June 2018) identified 24 unique reports on the topic (19 MTBI studies: 8 athletic, 5 military, 6 population-based; 5 CTE studies: 4 athletic and military, 1 leucotomy group). APOE-ε4 genotype is found to associate with outcomes in 4/8 athletic reports, 3/5 military reports, and 5/6 population-based reports following MTBI. Evidence on the association between APOE-ε4 and CTE from case series is equivocal. Refining modalities to aid CTE diagnosis in larger samples is needed in MTBI.

Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease.

The modulation of the brain endocannabinoid system has been identified as an option to treat neurodegenerative diseases including Parkinson's disease (PD). Especially the elevation of endocannabinoid levels by inhibition of hydrolytic degradation represents a valuable approach. To evaluate whether monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) inhibition could be beneficial for PD, we examined in parallel the therapeutic potential of the highly selective MAGL inhibitor KML29 elevating 2-arachidonoylglyerol (2-AG) levels and the highly selective FAAH inhibitor PF-3845 elevating anandamide (AEA) levels in a chronic methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/probenecid) mouse model of PD. Chronic administration of KML29 (10 mg/kg) but not PF-3845 (10 mg/kg) attenuated striatal MPTP/probenecid-induced dopamine depletion. Furthermore, KML29 induced an increase in Gdnf but not Bdnf expression, whereas PF-3845 decreased the MPTP/probenecid-induced Cnr2 expression without any effects on neurotrophin expression. Investigation of treatment-naïve striatal mRNA levels revealed a high presence of Gdnf and Mgll in contrast to Bdnf and Faah. Treatment of primary mouse microglia with 2-AG increased Gdnf but not Bdnf expression, suggesting that microglia might mediate the observed KML29-induced increase in Gdnf. In summary, pharmacological MAGL but not FAAH inhibition in the chronic MPTP/probenecid model attenuated the MPTP/probenecid-induced effects on striatal dopamine levels which were accompanied by an increase in 2-AG levels.

Comparison of Sirtuin 3 Levels in ALS and Huntington's Disease-Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models.

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington's disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.