New Nature PD Model: Disrupting the function of mitochondrial complex I is sufficient to induce progressive Parkinson's disease

Written | Qi Parkinson's disease (PD) is the second most common neurodegenerative disease.
The motor dysfunction in patients is mainly caused by the loss of dopaminergic neurons in the substantia nigra (SN)
.

Although the pathogenic factors of PD are diverse, a number of evidences show the importance of mitochondrial dysfunction.
For example, mutations in the PARK7, PARK6, and PARK2 genes that code for maintaining mitochondrial quality control proteins can cause early-onset PD [1]
.

The susceptibility of dopaminergic neurons to mitochondrial dysfunction can be partly attributed to their high metabolic demand, which causes the continuous stimulation of mitochondrial oxidative phosphorylation (OXPHOS).
However, this huge energy supply comes at the cost of increased mitochondrial oxidative damage
.

Autopsy studies have shown that the loss of mtDNA integrity in the SN of PD patients is related to the loss of functional mitochondrial complex I (MCI)
.

However, whether this MCI-acquired injury is a by-product of the PD disease process or a driving factor of the disease is still unknown
.

On November 3, 2021, D.
James Surmeier’s team from Northwestern University’s Feinberg School of Medicine published an article in the journal Nature entitled Disruption of mitochondrial complex I induces progressive parkinsonism.
This study uses selective destruction of mice MCI function in dopaminergic neurons, found that MCI dysfunction is sufficient to cause progressive Parkinson’s disease-related motor deficits, and different types of motor function impairments (fine movements and gross movements) and different parts (striatum and substantia nigra) dopamine The relevance of the release challenges the long-standing view on the motor symptoms of the disease
.

To prove whether MCI dysfunction is a driving factor of PD, the team specifically knocked out the Ndufs2 gene, which encodes the catalytic core subunit of MCI, from mouse dopaminergic neurons
.

cNdufs2-/- mice still showed normal gross motor behavior at 20 days after birth (P20)
.

However, in the following 10 days, the mitochondria in SN dopaminergic neurons became net consumers of ATP rather than producers, and the mitochondrial cristae structure changed significantly
.

The RiboTag method was used to isolate mRNA from dopaminergic neurons and sequenced.
It was found that cNdufs2-/- mice had a metabolic reprogramming similar to the Warburg effect, that is, genes encoding glycolytic proteins were up-regulated, and compared with OXPHOS and encoding The glycolysis inhibitor gene is down-regulated
.

In addition to triggering metabolic reprogramming, the team also found that the loss of Ndufs2 can cause significant changes in the expression of genes related to axon growth and transport, synaptic conduction, dopamine (DA) synthesis and storage
.

The liquid chromatography and mass spectrometry analysis of the striatum tissue further verified that the DA synthesis of the cNdufs2-/- mouse striatum was significantly reduced.
In addition, the current of the cyclic nucleotide-gated cation channel that helps drive pacing was also significantly reduced.

.

By P60, the loss of axon protein associated with dopaminergic signals is enlarged from the dorsal striatum to the ventral striatum, and the tyrosine hydroxyl in the dendritic region of the cNdufs2-/- mouse SN dopaminergic neuron cell body The expression of amylase decreased to about half of the control group, and the release of DA decreased by about 75%
.

Compared with the traditional PD model in which DA is rapidly depleted in the entire basal ganglia, the pathological staging of cNdufs2-/- mice can assess how the regional defects of DA release are related to behavior
.

As the release of DA from the dorsal striatum drops to near the detection threshold at around P30, cNdufs2-/- mice lose the ability to perform associative learning tasks.
Interestingly, this task can be recovered by levodopa treatment at P30.
The treatment of P60 cannot be restored
.

In an experiment to evaluate fine motor skills by the time it takes the mice to remove the adhesive from the front paws, cNdufs2-/- mice have significantly longer time to complete the task, and they also show poorer open-field exploration behavior
.

In addition, cNdufs2-/- mice of P60 showed only slight gait disturbance, and at P100 would they show features such as open hind limbs, abnormal paw position, and change in stride length
.

During P120-150, about 40% of SN dopaminergic neurons were lost
.

It should be noted that cNdufs2-/- mice developed gross motor behavior deficits in the later stage, which paralleled the changes in the release of SN DA instead of dorsal striatum DA
.

Although there is clear clinical evidence that striatal DA depletion is necessary for motor retardation and stiffness in PD patients [2], its adequacy has never been fully tested because traditional PD models often lead to DA in the entire basal ganglia.
The rapid depletion
.

Here, observations of cNdufs2-/- mice show that the loss of DA release from the dorsal striatum is sufficient to produce motor learning and fine motor deficits, but it does not reach the level of motor symptoms similar to clinical PD
.

The team confirmed the release of dopamine from the substantia nigra by stereotactic injection of AAV carrying AADC (which can convert levodopa into DA) into the mouse dorsal striatum or SN, and subsequent analysis of the mouse's open-field gait.
Loss is a necessary factor for gross motor deficits
.

Overall, this study not only demonstrated that the loss of MCI function in dopaminergic neurons is sufficient to trigger progressive, axon-first loss of function and levodopa-responsive Parkinson's disease, but also that DA depletion in the dorsal striatum It is necessary for associative motor learning and fine motor, but the DA release defect of the substantia nigra can cause gross motor injury characteristics similar to those of clinical PD patients
.

In response to this research, Zak Doric and Ken Nakamura from the Gladstone Institute in the United States published an opinion article Principles of Parkinson's disease disputed by model in the same journal 
.

They pointed out that the mouse model of Parkinson’s disease based on mitochondrial dysfunction constructed by González-Rodríguez et al.
represents one of the best models of sporadic PD currently available.
It can not only study the role of complex I deficiency in the disease, but also provide A model to evaluate the potential of treatment strategies
.

In addition, a distinctive feature of this model is that dopamine neurons degenerate progressively in a few months, and there is a delay in the degeneration of axons and cell bodies.
This delay is convenient for detailed study of the effects of dopamine damage at two different locations
.

Another considerable improvement is that the model confirms that reduced striatal dopamine release is necessary and insufficient for motor deficits, that is, substantia nigra dopamine plays a vital role in maintaining gross movement
.

Original link: https://doi.
org/10.
1038/s41586-021-04059-0 https://doi.
org/10.
1038/d41586-021-02955-z Plate maker: Eleven References 1.
Beilina, A.
& Cookson, MR Genes associated with Parkinson's disease: regulation of autophagy and beyond.
J.
Neurochem.
139, 91–107 (2016).
2.
Wichmann, T.
Changing views of the pathophysiology of parkinsonism.
Mov.
Disord.
34, 1130– 1143 (2019).
Reprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.

BioArt reserves all statutory rights and offenders must be investigated
.