Postmortem neuropathology in early Huntington disease.

Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.

Direct Reprogramming of Somatic Skin Cells from a Patient with Huntington's Disease into Striatal Neurons to Create Models of Pathology.

A new in vitro model of Huntington's disease (HD) was developed via a direct reprogramming of dermal fibroblasts from HD patients into striatal neurons. A reprogramming into induced pluripotent stem (iPS) cells is obviated in the case of direct reprogramming, which thus yields neurons that preserve the epigenetic information inherent in cells of a particular donor and, consequently, the age-associated disease phenotype. A main histopathological feature of HD was reproduced in the new model; i.e., aggregates of mutant huntingtin accumulated in striatal neurons derived from a patient's fibroblasts. Experiments with cultured neurons obtained via direct reprogramming make it possible to individually assess the progression of neuropathology and to implement a personalized approach to choosing the treatment strategy and drugs for therapy. The in vitro model of HD can be used in preclinical drug studies.

Effect of safranal or candesartan on 3-nitropropionicacid-induced biochemical, behavioral and histological alterations in a rat model of Huntington's disease.

3-nitropropionic acid (3-NP) is a potent mitochondrial inhibitor mycotoxin. Systemic administration of 3-NP can induce Huntington's disease (HD)-like symptoms in experimental animals. Safranal (Safr) that is found in saffron essential oil has antioxidant, anti-inflammatory and anti-apoptotic actions. Candesartan (Cands) is an angiotensin receptor blocker that has the potential to prevent cognitive deficits. The present study aims to investigate the potential neuroprotective efficacy of Safr or Cands in 3-NP-induced rat model of HD. The experiments continued for nine consecutive days. Rats were randomly assigned into seven groups. The first group (Safr-control) was daily intraperitoneally injected with paraffin oil. The second group (Cands- and 3-NP-control) daily received an oral dose of 0.5% carboxymethylcellulose followed by an intraperitoneal injection of 0.9% saline. The third and fourth groups received a single daily dose of 50 mg/kg Safr (intraperitoneal) and 1 mg/kg Cands (oral), respectively. The sixth group was daily treated with 50 mg Safr kg/day (intraperitoneal) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The seventh group was daily treated with 1 mg Cands /kg/day (oral) and was intraperitoneally injected with 20 mg 3-NP/ kg, from the 3rd till the 9th day. The present results revealed that 3-NP injection induced a considerable body weight loss, impaired memory and locomotor activity, reduced striatal monoamine levels. Furthermore, 3-NP administration remarkably increased striatal malondialdehyde and nitric oxide levels, whereas markedly decreased the total antioxidant capacity. Moreover, 3-NP significantly upregulated the activities of inducible nitric oxide synthase and caspase-3 as well as the Fas ligand, in striatum. On the contrary, Safr and Cands remarkably alleviated the above-mentioned 3-NP-induced alterations. In conclusion, Safr and Cands may prevent or delay the progression of HD and its associated impairments through their antioxidant, anti-inflammatory, anti-apoptotic and neuromodulator effects.

Secondary neurodegeneration of ipsilateral substantia nigra in acute ischemic stroke.

INTRODUCTION: Secondary neurodegeneration after stroke is a complex phenomenon affecting remote and synaptically linked cerebral areas. The involvement of the substantia nigra in this process has been rarely described in infarcts involving the striatum. METHODS: We are presenting a case of ischemic stroke involving the right striatum due to atrial fibrillation and associated in a few days with the neuroimaging finding of hyperintensity of the ipsilateral substantia nigra and striatonigral tract on T2-fluid attenuated inversion recovery and diffusion-weighted imaging sequences of brain magnetic resonance imaging. This finding was not related to clinical manifestations and substantially disappeared within 3 months from stroke onset. DISCUSSION: The pathophysiology of secondary degeneration of the substantia nigra is poorly understood and it relies on animal models and autoptic studies. The main putative mechanism is not ischemic but excitotoxic with a different role of the internal and external globus pallidus and a different effect on the pars compacta and pars reticularis of the substantia nigra. In animal models, inflammatory mechanisms seem play a role only in the late phase. The main studies on humans were presented in detail. CONCLUSIONS: A better understanding of the secondary degeneration of the substantia nigra has the potentiality to offer a chance for neuroprotection in acute stroke, but further studies are needed.

Short-term hindlimb unloading negatively affects dopaminergic transmission in the nigrostriatal system of mice.

The nigrostriatal system composed of the dorsal striatum and the substantia nigra (SN) is highly involved in the control of motor behavior. Various extremal and pathological conditions as well as social isolation (SI) may cause an impairment of locomotor function; however, corresponding alterations in the nigrostriatal dopaminergic pathway are far from full understanding. Here, we analyzed the effect of 3-day hindlimb unloading (HU) and SI on the key players of dopamine transmission in the nigrostriatal system of CD1 mice. Three groups of mice were analyzed: group-housed (GH), SI, and HU animals. Our data showed a significant decrease in the expression and phosphorylation of tyrosine hydroxylase (TH) in the SN and dorsal striatum of HU mice that suggested attenuation of dopamine synthesis in response to HU. In the dorsal striatum of HU mice, the downregulation of TH expression was also observed indicating the effect of unloading; however, TH phosphorylation at Ser40 was mainly affected by SI pointing on an impact of isolation too. Expression of dopamine receptors D1 in the dorsal striatum of HU mice was increased suggesting a compensatory response, but the activity of downstream signaling pathways involving protein kinase A and cAMP response element-binding protein was inhibited. At the same time, SI alone did not affect expression of DA receptors and activity of downstream signaling in the dorsal striatum. Obtained data let us to conclude that HU was the main factor which impaired dopamine transmission in the nigrostriatal system but SI made some contribution to its negative effects.

Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington's disease.

Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K+ that underlie striatal hyperexcitability in HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation.

Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.

Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.

Host-to-graft Propagation of α-synuclein in a Mouse Model of Parkinson's Disease: Intranigral Versus Intrastriatal Transplantation.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies. Ectopic transplantation of human fetal ventral mesencephalic DA neurons into the striatum of PD patients have provided proof-of-principle for the cell replacement strategy in this disorder. However, 10 to 22 y after transplantation, 1% to 27% of grafted neurons contained α-syn aggregates similar to those observed in the host brain. We hypothesized that intrastriatal grafts are more vulnerable to α-syn propagation because the striatum is not the ontogenic site of nigral DA neurons and represents an unfavorable environment for transplanted neurons. Here, we compared the long-term host-to-graft propagation of α-syn in 2 transplantation sites: the SNpc and the striatum. METHODS: Two mouse models of PD were developed by injecting adeno-associated-virus2/9-human α-syn A53T into either the SNpc or the striatum of C57BL/6 mice. Mouse fetal ventral mesencephalic DA progenitors were grafted into the SNpc or into the striatum of SNpc or striatum of α-syn injected mice, respectively. RESULTS: First, we have shown a degeneration of the nigrostriatal pathway associated with motor deficits after nigral but not striatal adeno-associated-virus-hαsyn A53T injection. Second, human α-syn preferentially accumulates in striatal grafts compared to nigral grafts. However, no differences were observed for phosphorylated α-syn, a marker of pathological α-syn aggregates. CONCLUSIONS: Taken together, our results suggest that the ectopic site of the transplantation impacts the host-to-graft transmission of α-syn.

Dopamine-independent development and maintenance of mouse striatal medium spiny neuron dendritic spines.

Striatal medium spiny neurons (MSNs) and striatal dopamine (DA) innervation are profoundly important for brain function such as motor control and cognition. A widely accepted theory posits that striatal DA loss causes (or leads to) MSN dendritic atrophy. However, examination of the literature indicates that the data from Parkinson's disease (PD) patients and animal PD models were contradictory among studies and hard to interpret. Here we have re-examined the potential effects of DA activity on MSN morphology or lack thereof. We found that in 15-day, 4- and 12-month old Pitx3 null mutant mice that have severe DA denervation in the dorsal striatum while having substantial residual DA innervation in the ventral striatum, MSN dendrites and spine numbers were similar in dorsal and ventral striatum, and also similar to those in normal mice. In 15-day, 4- and 12-month old tyrosine hydroxylase knockout mice that cannot synthesize L-dopa and thus have no endogenous DA in the entire brain, MSN dendrites and spine numbers were also indistinguishable from age-matched wild-type (WT) mice. Furthermore, in adult WT mice, unilateral 6-OHDA lesion at 12 months of age caused an almost complete striatal DA denervation in the lesioned side, but MSN dendrites and spine numbers were similar in the lesioned and control sides. Taken together, our data indicate that in mice, the development and maintenance of MSN dendrites and spines are DA-independent such that DA depletion does not trigger MSN dendritic atrophy; our data also suggest that the reported MSN dendritic atrophy in PD may be a component of neurodegeneration in PD rather than a consequence of DA denervation.

Restorative cell and gene therapies for Parkinson's disease.

One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by l-dopa containing drugs leads to the genesis of l-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.

Miniature-swine iPSC-derived GABA progenitor cells function in a rat Parkinson's disease model.

Induced pluripotent stem cells (iPS cells) are considered a promising source of cell-based therapy for the treatment of Parkinson's disease (PD). Recent studies have shown forebrain GABA interneurons have crucial roles in many psychiatric disorders, and secondary changes in the GABA system play a directly effect on the pathogenesis of PD. Here, we first describe an efficient differentiation procedure of GABA progenitors (MiPSC-iGABAPs) from miniature-swine iPSCs through two major developmental stages. Then, the MiPSC-iGABAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of 6-hydroxydopamine (OHDA)-lesioned PD model rats to confirm their feasibility for the neural transplantation as a donor material. Furthermore, the grafted MiPSC-iGABAPs could survive and migrate from the graft site into the surrounding brain tissue including striatum (ST) and substantia nigra (SN) for at least 32 weeks, and significantly improved functional recovery of PD rats from their parkinsonian behavioral defects. Histological studies showed that the grafted cells could migrate and differentiate into various neurocytes, including GABAergic, dopaminergic neurons, and glial cells in vivo, and many induced dopaminergic neurons extended dense neurites into the host striatum. Moreover, over 50% of the grafted MiPSC-iGABAPs could express GABA, and these GABAergic neurons might be responsible for modifying the balance of excitatory and inhibitory signals in the striatum to promote behavioral recovery. Thus, the present study confirmed that the MiPSC-iGABAPs can be used as an attractive donor material for the neural grafting to remodel basal ganglia circuitry in neurodegenerative diseases, avoiding tumorigenicity of iPSCs and the nonproliferative and nondifferentiated potential of mature neurons.

Progressive Degeneration and Adaptive Excitability in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons Exposed to HIV-1 Tat and Morphine.

The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48 h of Tat exposure, D1 MSN firing rates decreased below control (Tat-) levels following 2 weeks and 1 month of Tat exposure but returned to control levels after 2 months. D2 neurons continued to display Tat-dependent increases in excitability at 2 weeks, but also returned to control levels following 1 and 2 months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2 months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.

A Neuropsychiatric and Neuroimaging Study of Unilateral and Bilateral Striatal Ischemic Lesions.

OBJECTIVE: Neuropsychiatric disorders after striatal territory stroke have not been studied systematically. The investigators aimed to study the spectrum of cognitive and behavioral disorders following striatal infarcts. METHODS: Different aspects of cognitive functions, including executive, frontal lobe, memory, visuospatial, language, and semantic processing, were assessed among patients with striatal infarct. Structural MRI data sets were obtained 3 months after stroke to delineate affected territories of the striatum. MRIcroGL software was used to acquire multiple layers of images, generate volume renderings, and draw volumes of interest. To determine the brain locus most frequently affected in patients with distinct cognitive disorders, ischemic area distributions in patients with cognitive dysfunction versus those without cognitive impairment were contrasted. RESULTS: Among 60 patients in this study, six different striatal infarction types were significantly associated with seven different cognitive categories (p<0.001). Unilateral caudate lesion was characterized by attention, planning, and executive disorders (38%), and unilateral lentiform infarct was characterized by executive (36%) and frontal (36%) dysfunctions. Bilateral caudate infarcts caused impairments in frontal and executive functions (75%), as well as in autobiographical (50%) and episodic (50%) memory. In those with bilateral caudate plus lentiform infarcts, all components of frontal and executive functions were dramatically impaired. The anteromedial striatum was affected more frequently in patients with language impairment compared with patients with other types of cognitive dysfunction (p<0.001). CONCLUSIONS: Following striatal stroke, a wide range of frontal-like cognitive impairments occurred, along with impaired working memory, declarative memory, executive function, speech fluency, and motor function.

Cytology, architecture, development, and connections of the primate striatum: Hints for human pathology.

Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography patterns that are distinct for Huntington's disease, Parkinson's disease, or the Tauopathies. These patterns of neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, and chemical factors studied in human and non-human primates, that may underlie potential differences in selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate striatal pathology in humans.

Phase-adaptive brain stimulation of striatal D1 medium spiny neurons in dopamine-depleted mice.

Brain rhythms are strongly linked with behavior, and abnormal rhythms can signify pathophysiology. For instance, the basal ganglia exhibit a wide range of low-frequency oscillations during movement, but pathological "beta" rhythms at ~ 20 Hz have been observed in Parkinson's disease (PD) and in PD animal models. All brain rhythms have a frequency, which describes how often they oscillate, and a phase, which describes the precise time that peaks and troughs of brain rhythms occur. Although frequency has been extensively studied, the relevance of phase is unknown, in part because it is difficult to causally manipulate the instantaneous phase of ongoing brain rhythms. Here, we developed a phase-adaptive, real-time, closed-loop algorithm to deliver optogenetic stimulation at a specific phase with millisecond latency. We combined this Phase-Adaptive Brain STimulation (PABST) approach with cell-type-specific optogenetic methods to stimulate basal ganglia networks in dopamine-depleted mice that model motor aspects of human PD. We focused on striatal medium spiny neurons expressing D1-type dopamine receptors because these neurons can facilitate movement. We report three main results. First, we found that our approach delivered PABST within system latencies of 13 ms. Second, we report that closed-loop stimulation powerfully influenced the spike-field coherence of local brain rhythms within the dorsal striatum. Finally, we found that both 4 Hz PABST and 20 Hz PABST improved movement speed, but we found differences between phase only with 4 Hz PABST. These data provide causal evidence that phase is relevant for brain stimulation, which will allow for more precise, targeted, and individualized brain stimulation. Our findings are applicable to a broad range of preclinical brain stimulation approaches and could also inform circuit-specific neuromodulation treatments for human brain disease.

The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257A Mitochondrial Mutator Mice.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial Complex I and IV activities, although we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257A mtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin-/-/PolgAD257A/D257A mice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENT Producing a mouse model of Parkinson's disease (PD) that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin-/-/PolgAD257A/D257A mice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin-/-/PolgAD257A/D257A mice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.

Connectivity of the corticostriatal and thalamostriatal systems in normal and parkinsonian states: An update.

The striatum receives abundant glutamatergic afferents from the cortex and thalamus. These inputs play a major role in the functions of the striatal neurons in normal conditions, and are significantly altered in pathological states, such as Parkinson's disease. This review summarizes the current knowledge of the connectivity of the corticostriatal and thalamostriatal pathways, with emphasis on the most recent advances in the field. We also discuss novel findings regarding structural changes in cortico- and thalamostriatal connections that occur in these connections as a consequence of striatal loss of dopamine in parkinsonism.

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

Striatal Blood-Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study.

BACKGROUND: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. OBJECTIVE: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. METHODS: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.