Cerebellum in neurodegenerative diseases: Advances, challenges, and prospects.

Neurodegenerative diseases (NDs) are a group of neurological disorders characterized by the progressive dysfunction of neurons and glial cells, leading to their structural and functional degradation in the central and/or peripheral nervous system. Historically, research on NDs has primarily focused on the brain, brain stem, or spinal cord associated with disease-related symptoms, often overlooking the role of the cerebellum. However, an increasing body of clinical and biological evidence suggests a significant connection between the cerebellum and NDs.

Patch and matrix striatonigral neurons differentially regulate locomotion.

The striatonigral neurons are known to promote locomotion. These neurons reside in both the patch (also known as striosome) and matrix compartments of the dorsal striatum. However, the specific contribution of patch and matrix striatonigral neurons to locomotion remain largely unexplored.

Patch and matrix striatonigral neurons differentially regulate locomotion.

Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier and , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion.

Progress on early diagnosing Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions. The disease follows a continuum, starting with preclinical stages, progressing to mild cognitive and behavioral impairment, ultimately leading to dementia. Early detection of AD is crucial for better diagnosis and more effective treatment.

Pathological characteristics of axons and proteome patterns in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

Background: Although mutations have been linked to -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the effects of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. By examining pathological and molecular alterations, we hope to better understand the disease process.

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson's Disease-Associated Neurodegeneration.

The degeneration of midbrain dopaminergic (mDA) neurons, particularly in the substantia nigra pars compacta (SNc), is one of the most prominent pathological hallmarks of Parkinson's disease (PD). To uncover the pathogenic mechanisms of mDA neuronal death during PD may provide therapeutic targets to prevent mDA neuronal loss and slow down the disease's progression. Paired-like homeodomain transcription factor 3 (Pitx3) is selectively expressed in the mDA neurons as early as embryonic day 11.

Deficiency of Perry syndrome-associated p150 in midbrain dopaminergic neurons leads to progressive neurodegeneration and endoplasmic reticulum abnormalities.

Multiple missense mutations in p150 are linked to Perry syndrome (PS), a rare neurodegenerative disease pathologically characterized by loss of nigral dopaminergic (DAergic) neurons. Here we generated p150 conditional knockout (cKO) mice by deleting p150 in midbrain DAergic neurons. The young cKO mice displayed impaired motor coordination, dystrophic DAergic dendrites, swollen axon terminals, reduced striatal dopamine transporter (DAT), and dysregulated dopamine transmission.

Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.

Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs).

Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS.

Mutations in Cu/Zn-superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we determined the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms.

Low-level overexpression of wild type TDP-43 causes late-onset, progressive neurodegeneration and paralysis in mice.

Modestly increased expression of transactive response DNA binding protein (TDP-43) gene have been reported in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neuromuscular diseases. However, whether this modest elevation triggers neurodegeneration is not known. Although high levels of TDP-43 overexpression have been modeled in mice and shown to cause early death, models with low-level overexpression that mimic the human condition have not been established.

The essential role of transcription factor Pitx3 in preventing mesodiencephalic dopaminergic neurodegeneration and maintaining neuronal subtype identities during aging.

Pituitary homeobox 3 (Pitx3) is required for the terminal differentiation of nigrostriatal dopaminergic neurons during neuronal development. However, whether Pitx3 contributes to the normal physiological function and cell-type identity of adult neurons remains unknown. To explore the role of Pitx3 in maintaining mature neurons, we selectively deleted Pitx3 in the mesodiencephalic dopaminergic (mdDA) neurons of Pitx3DAT bigenic mice using a tamoxifen inducible Cre gene-targeting system.

Diverse midbrain dopaminergic neuron subtypes and implications for complex clinical symptoms of Parkinson's disease.

Parkinson's disease (PD), the most common degenerative movement disorder, is clinically manifested with various motor and non-motor symptoms. Degeneration of midbrain (SNc) dopaminergic neurons (DANs) is generally attributed to the motor syndrome. The underlying neuronal mechanisms of non-motor syndrome are largely unexplored.

Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's Disease.

Dopamine is an important chemical messenger in the brain, which modulates movement, reward, motivation, and memory. Different populations of neurons can produce and release dopamine in the brain and regulate different behaviors. Here we focus our discussion on a small but distinct group of dopamine-producing neurons, which display the most profound loss in the ventral of patients with Parkinson's disease.

Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease.

The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality.

Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration.

Vacuole membrane protein 1 (VMP1), the endoplasmic reticulum (ER)-localized autophagy protein, plays a key role during the autophagy process in mammalian cells. To study the impact of VMP1-deficiency on midbrain dopaminergic (mDAergic) neurons, we selectively deleted VMP1 in the mDAergic neurons of VMP1/DAT bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1/DAT mice developed progressive motor deficits, concomitant with a profound loss of mDAergic neurons in the substantia nigra pars compacta (SNc) and a high presynaptic accumulation of α-synuclein (α-syn) in the enlarged terminals.

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear.

α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism.

The nuclear receptor-related 1 protein (Nurr1) is critical for the development and survival of midbrain dopamine neurons that are predominantly affected and progressively degenerated in Parkinson's disease (PD). The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored.

Nurr1 conditional knockout mice display inflammatory injury to nigrostriatal dopaminergic neurons.

Nuclear receptor-related 1 protein (NURR1) is essential for the development and maintenance of midbrain dopaminergic (DAergic) neurons. NURR1 also protects DAergic neurons against neuroinflammation. However, it remains to be determined to what extent does NURR1 exerts its protective function through acting autonomously in the microglia.

Correction to: Parkinson's disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging.

The original article had mistakenly inverted co-author, Wang Zheng's name. This has since been corrected.

Parkinson's disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging.

Background: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons.

Distinct Connectivity and Functionality of Aldehyde Dehydrogenase 1a1-Positive Nigrostriatal Dopaminergic Neurons in Motor Learning.

Parkinson's disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1 nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1 nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs).

Unbalanced calcium channel activity underlies selective vulnerability of nigrostriatal dopaminergic terminals in Parkinsonian mice.

Dopamine (DA) release in striatum is functionally segregated across a dorsolateral/ventromedial axis. Interestingly, nigrostriatal DA signaling disruption in Parkinson's disease (PD) preferentially affects the dorsolateral striatum. The relationship between afferent presynaptic calcium transients (PreCaTs) in DA terminals and DA release in dorsolateral (Caudato-Putamen, DLS) and ventromedial (Nucleus Accumbens Shell, VS) striatal subregions was examined by ex vivo real-time dual-recording in conditional transgenic mice expressing the calcium indicator protein GCaMP3.

ALDH1A1 regulates postsynaptic μ-opioid receptor expression in dorsal striatal projection neurons and mitigates dyskinesia through transsynaptic retinoic acid signaling.

Aldehyde dehydrogenase 1A1 (ALDH1A1), a retinoic acid (RA) synthase, is selectively expressed by the nigrostriatal dopaminergic (nDA) neurons that preferentially degenerate in Parkinson's disease (PD). ALDH1A1-positive axons mainly project to the dorsal striatum. However, whether ALDH1A1 and its products regulate the activity of postsynaptic striatal neurons is unclear.

Coding mutations in contribute to Parkinson's disease.

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD.