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New articles from Prof. Huaibin Cai, our Editorial Board Member

Published on: 20 Oct 2021 Viewed: 363

Our staff editors continue to share exciting, interesting, and thought-provoking reads in this recommended articles series.

This week, we would like to share several latest articles from Prof. Huaibin Cai, our Editorial Board Member.

Title: Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson’s Disease
Authors: Kathleen Carmichael, Rebekah C. Evans, Elena Lopez, Lixin Sun, Mantosh Kumar, Jinhui Ding, Zayd M. Khaliq, Huaibin Cai
Type: Review Article of Frontiers in Neural Circuits
Abstract:
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 substantia nigra pas compacta of patients with Parkinson’s disease. This group of dopaminergic neurons can be readily identified by a selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and accounts for 70% of total nigrostriatal dopaminergic neurons in both human and mouse brains. Recently, we presented the first whole-brain circuit map of these ALDH1A1-positive dopaminergic neurons and reveal an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. In this review, we first summarize previous findings of ALDH1A1-positive nigrostriatal dopaminergic neurons and their connectivity and functionality, and then provide perspectives on how the activity of ALDH1A1-positive nigrostriatal dopaminergic neurons is regulated through integrating diverse presynaptic inputs and its implications for potential Parkinson’s disease treatment.
Access this article: https://doi.org/10.3389/fncir.2021.644776


Title: Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration
Authors: Panpan Wang, Xi Chen, Yuanyuan Wang, Congcong Jia, Xinyao Liu, Ying Wang, Haifeng Wu, Huaibin Cai, Han-Ming Shen, Weidong Le
Type: Article of Cell Death & Disease
Abstract:
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 VMP1fl/fl/DATCreERT2 bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1fl/fl/DATCreERT2 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. Mechanistic studies showed that VMP1 deficiency in the mDAergic neurons led to the increased number of microtubule-associated protein 1 light chain 3-labeled (LC3) puncta and the accumulation of sequestosome 1/p62 aggregates in the SNc neurons, suggesting the impairment of autophagic flux in these neurons. Furthermore, VMP1 deficiency resulted in multiple cellular abnormalities, including large vacuolar-like structures (LVSs), damaged mitochondria, swollen ER, and the accumulation of ubiquitin+ aggregates. Together, our studies reveal a previously unknown role of VMP1 in modulating neuronal survival and maintaining axonal homeostasis, which suggests that VMP1 deficiency might contribute to mDAergic neurodegeneration via the autophagy pathway.
Access this article: https://doi.org/10.1038/s41419-021-03412-5


Title: Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson’s Disease
Authors: Jie Dong, Sarah Hawes, Junbing Wu, Weidong Le, Huaibin Cai
Type: Systematic Review Article of Frontiers in Neural Circuits
Abstract:
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. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.
Access this article: https://doi.org/10.3389/fncir.2021.645287


Title: Low-level overexpression of wild type TDP-43 causes late-onset, progressive neurodegeneration and paralysis in mice
Authors: Chunxing Yang, Tao Qiao, Jia Yu, Hongyan Wang, Yangsu Guo, Johnny Salameh, Jake Metterville, Sepideh Parsi, Robert H. Brown, Huaibin Cai, Zuoshang Xu
Type: Research Article of Research Square
Abstract:
Background
Modestly elevated levels 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. In this study, we tried to fill this knowledge gap.
Methods
Transgenic mice overexpressing wild type TDP-43 at less than 60% above the endogenous CNS levels were constructed, and their phenotypes were analyzed by a variety of techniques, including biochemical, molecular, histological, behavioral techniques and electromyography.
Results
The TDP-43 transgene was expressed in neurons, astrocytes, and oligodendrocytes in the cortex and predominantly in astrocytes and oligodendrocytes in the spinal cord. The mice developed a reproducible progressive weakness ending in paralysis in mid-life. Detailed analysis showed ~30% loss of large pyramidal neurons in the layer V motor cortex; in the spinal cord, severe demyelination was accompanied by oligodendrocyte injury, protein aggregation, astrogliosis and microgliosis, and elevation of neuroinflammation. Surprisingly, there was no loss of lower motor neurons in the lumbar spinal cord despite the complete paralysis of the hindlimbs. However, denervation was detected at the neuromuscular junction.
Conclusions
Low-level TDP-43 overexpression can cause diverse aspects of ALS, including late-onset and progressive motor dysfunction, neuroinflammation, and neurodegeneration. These results demonstrate that modest elevations in TDP-43 expression may underlie not only ALS but also other neuromuscular disorders involving TDP-43 proteinopathy. Because of the predictable and progressive clinical paralytic phenotype, this transgenic mouse model may also be useful in preclinical trial of therapeutics targeting neurological disorders associated with elevated levels of TDP-43.
Access this article: https://doi.org/10.21203/rs.3.rs-455895/v1


Title: Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson’s disease-related α-synuclein A53T mice
Authors: Luyan Jiao, Meige Zheng, Jinhai Duan, Ting Wu, Zhao Li, Lin Liu, Xianhong Xiang, Xiaolu Tang, Jinyang He, Xingjian Li, Guofeng Zhang, Jinhui Ding, Huaibin Cai, Xian Lin
Type: Research Article of The FASEB Journal
Abstract:
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. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.
Access this article: https://doi.org/10.1096/fj.202000017RR


Title: Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging
Authors: Xi Chen, Chengsong Xie, Wotu Tian, Lixin Sun, Wang Zheng, Sarah Hawes, Lisa Chang, Justin Kung, Jinhui Ding, Shengdi Chen, Weidong Le, Huaibin Cai
Type: Research Article of Molecular Neurodegeneration
Abstract:
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. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined.
Methods
We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2−/−) and control (Lrrk2+/+) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2+/+ and Lrrk2−/− mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2+/+ and Lrrk2−/− mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice.
Results
Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2−/− striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2−/− and R1441C SPNs.
Conclusions
Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.
Access this article: https://doi.org/10.1186/s13024-020-00360-0

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