Sci Adv︱ The latest evidence that neurodevelopmental defects cause juvenile Parkinson's disease: patients with DNAJC6 mutations have neurodevelopmental defects and neurodegenerative phenotypes in the brains

And explore the mystery of neuroscience with rigorous academic and logical thinking︱Editor by Wang Sizhen︱Wang Sizhen Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the loss of dopamine neurons in the substantia nigra.
Alpha-synuclein (α-syn) aggregation, mitochondrial dysfunction, vesicle transport defects, and impaired endolysosome degradation are the basic pathological features of PD [1].

 DNAJC6 gene, full name DNAJ/HSP40 homolog C subfamily member 6, encodes auxin, as a common partner, HSC70 can be recruited into clathrin-coated vesicles for decomposition [2].

DNAJC6 loss-of-function mutations are related to familial juvenile or early-onset PD, but the pathogenesis of juvenile PD caused by DNAJC6 mutations is unclear [3-4].

 Generally, we think that PD is an age-related neurodegenerative disease.
However, neurodevelopment may also contribute to the pathogenesis of PD.
For example, PD patients with DNAJC6 mutations develop the disease in adolescence, and most of them are 10 years old.
Years old or older, but there is still a lack of strong evidence of development [3-4].So, what role does the DNAJC6 gene play in the pathogenesis of PD? On February 17, 2021, "Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations" is the latest research paper published online on Science Advances, the Sang-Hun Lee project of Hanyang University School of Medicine, Korea The group and the Seung-Jae Lee 4 research group of the Institute of Neuroscience of Seoul National University School of Medicine jointly explored this problem and found that there are neurodevelopmental defects and neurodegenerative phenotypes in the brains of PD patients with DNAJC6 mutations, including The development of dopamine neurons in the midbrain is abnormal, and the regulation of the WNT-LMX1A signaling pathway is not interrupted.

In this article, in order to specifically study the pathogenic role of DNAJC6 in PD, the author established a human embryonic stem cell model with DNAJC6 mutations through CRISPR-Cas9 gene editing technology, and induced them (mutant type and wild type) to the ventral side.
The brain organoids are differentiated, and the ventral midbrain is the main brain area affected by PD.

The results found that the DNAJC6 mutant ventral midbrain had obvious developmental defects (especially early developmental defects): the neural tube structure was incomplete, and the expression of multiple development-related genes was down-regulated, including LMX1A and EN1 (both of which are midbrain dopamine Regulators of early neuron development, the former is the main regulator), and NURR1 (a late developmental regulator), etc.

The main feature of PD is the loss of dopamine neurons, which suggests the importance of DNAJC6 mutation in the pathogenesis of PD.

At the same time, the author also noticed that after DNAJC6 is mutated, its mRNA will become unstable and easily degraded, so the overall mRNA level and protein level are relatively low, which is consistent with previous reports [3].

 In order to further understand the molecular basis of DNAJC6 mutation-mediated developmental defects, the authors performed RNA sequencing analysis.

It is found that the down-regulated genes caused by DNAJC6 mutations are mainly concentrated in the WNT signaling pathway, that is, mutations cause damage to the WNT signaling pathway.

The WNT signaling pathway is closely related to the development of midbrain dopamine neurons (especially early development) [5].

Damage to the WNT signaling pathway will further reduce the levels of LMX1A and EN1, and eventually lead to abnormal development of dopamine neurons.

In particular, the author also found that LMX1A will send positive feedback to regulate the WNT signaling pathway: a decrease in the level of LMX1A will in turn cause a decrease in the level of key genes in the WNT signaling pathway, and vice versa.

In other words, DNAJC6 mutations can cause abnormal self-regulation of the WINT-LAX1A signaling pathway, and this abnormal self-regulation under the background of DNAJC6 mutations will make the degeneration and death of dopamine neurons more obvious, which means that neurons are more susceptible to toxicity.
The invasion is more likely to cause the risk of PD.

 In advanced midbrain organoids and neural stem cells carrying DNAJC6 mutants, some pathological features of PD can be clearly detected, including α-syn lesions (such as increased protein expression, abnormal hydrolysis, abnormal aggregation, etc.
), stress markers Increased levels of substances (such as reactive oxygen species, etc.
) and abnormalities in mitochondrial dysfunction and autophagy-lysosomal degradation pathways.
Mitochondrial dysfunction contributes to the formation of misfolded α-syn and the generation of oxidative stress.
Autophagy- Abnormal or defective lysosomal degradation pathways cannot normally degrade and clear α-syn, resulting in abnormal aggregation of α-syn and causing PD phenotype.

Of course, pathological features also include defects in synaptic vesicle circulation and decreased dopamine release.

When DNAJC6 is knocked down, there will be similar results as mentioned above, including damage to the structural integrity of the neural tube, down-regulation of development-related genes, and PD pathological features such as α-syn aggregation.
This is most likely due to knockdown of DNAJC6 or mutations.
DNAJC6 will cause both mRNA and protein to be maintained at a relatively low level.

 At the end of the article, the authors found that increasing the expression of DNAJC6 can restore the WIN-LMX1A signaling pathway, improve the development of midbrain dopamine neurons, enhance neuronal survival, rescue mitochondrial dysfunction, and alleviate other PD phenotypes.

When the expression of LMX1A is increased, the abnormal autophagy-lysosomal degradation pathway is not improved, which indicates that the DNAJC6 gene plays a special role in the LMX1A-independent autophagy-lysosomal degradation of α-syn.

In addition, the authors observed that the DNAJC6 mutation can also cause defects in cortical nerve regeneration, which suggests that the mutation may cause extensive neurodevelopment (or regeneration) defects, but in PD, the mutation mainly leads to the development of midbrain dopamine neurons And the function is abnormal.

 Summary of the signal pathways caused by DNAJC6 mutations (or deletions) in PD (picture quoted from: Wulansari et al.
, Sci.
Adv.
2021; 7: eabb1540) Conclusion and discussion of the article due to the lack of animal models that can accurately replicate the PD phenotype, and The limitations of obtaining samples from patients, the mechanism of juvenile or early-onset PD with DNAJC6 mutations is not thoroughly understood [6].

This study established an in vitro organoid disease model of human DNAJC6-PD, and early developmental mutations (or deletions) of DNAJC6 can cause midbrain dopamine neurons to be prone to neurodegeneration, accompanied by multiple PD phenotypes, and lead to WINT -Abnormality of the LMX1A signal path (above).

 Studies have also found that the loss of DNAJC6 function leads to mitochondrial dysfunction and damage to the autophagy-lysosomal degradation pathway, which in turn leads to the production of abnormally folded α-syn and the accumulation of pathological α-syn, which in turn makes neurons more susceptible to toxicity Damage (above).

 Although neurodevelopment is also considered to be an important factor in the pathogenesis of PD, there is a lack of strong evidence [3-4].

This study is a good indication that developmental defects may be a key factor leading to PD in adolescence.

Therefore, in the future related work, especially in the mechanism research, clinical diagnosis, and drug treatment of adolescents or early PD, the neurodevelopmental aspect cannot be ignored (above).

Original link: https://advances.
sciencemag.
org/content/7/8/eabb1540.
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Poewe, K.
Seppi, CM Tanner, GM Halliday, P.
Brundin, J.
Volkmann, AE Schrag, AE Lang, Parkinson disease.
Nat.
Rev.
Dis.
Primers.
3, 17013 ( 2017).
【2】E.
Ungewickell, H.
Ungewickell, SE Holstein, R.
Lindner, K.
Prasad, W.
Barouch, B.
Martin, LE Greene, E.
Eisenberg, Role of auxilin in uncoating clathrin-coated vesicles.
Nature 378, 632–635 (1995).
[3] S.
Edvardson,Y.
Cinnamon, A.
Ta-Shma, A.
Shaag, YI Yim, S.
Zenvirt, C.
Jalas, S.
Lesage, A.
Brice, A.
Taraboulos, KH Kaestner, LE Greene, O.
Elpeleg, A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism.
PLOS ONE 7, e36458 (2012).
[4] S.
Olgiati, M.
Quadri, M.
Fang, JP Rood, JA Saute , HF Chien, CG Bouwkamp, ​​Graafland, M.
Minneboo, GJ Breedveld, J.
Zhang; International Parkinsonism Genetics Network, FW Verheijen, AJ Boon, AJ Kievit, LB Jardim, W.
Mandemakers, ER Barbosa, CR Rieder, KL Leenders, J.
Wang, V.
Bonifati, DNAJC6 mutations associated with early-onset Parkinson's disease.
Ann.
Neurol.
79, 244–256 (2016).
[5] MT Alves dos Santos, MP Smidt, En1 and Wnt signaling in midbrain dopaminergic neuronal development.
Neural Dev.
6, 23 (2011) YI Yim, T.
Sun, LG Wu, A.
Raimondi, P.
De Camilli, E.
Eisenberg, LE Greene, Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice.
Proc.
Natl.
Acad.
Sci.
USA 107, 4412–4417 (2010).
[6] M.
Decressac, N.
Volakakis, A.
Bjorklund, T.
Perlmann, NURR1 in Parkinson disease—From pathogenesis to therapeutic potential.
Nat.
Rev.
Neurol.
9, 629–636 (2013).
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