2019年ALS/FTD十大基础研究进展

1. Nat Med—脊髓软膜下输送AAV9-shRNA具有广泛的基因沉默作用并可阻断ALS的神经变性过程

英文摘要：

Genesilencing with virally delivered shRNA represents a promising approach fortreatment of inherited neurodegenerative disorders. In the present study wedevelop a subpial technique, which we show in adult animals successfullydelivers adeno-associated virus (AAV) throughout the cervical, thoracic andlumbar spinal cord, as well as brain motor centers. One-time injection atcervical and lumbar levels just before disease onset in mice expressing afamilial amyotrophic lateral sclerosis(ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease,including near-complete preservation of spinal α-motoneurons and muscleinnervation. Treatment after disease onset potently blocks progression of diseaseand further α-motoneuron degeneration. A single subpial AAV9 injection in adultpigs or non-human primates using a newly designed device produces homogeneousdelivery throughout the cervical spinal cord white and gray matter and brainmotor centers. Thus, spinal subpial delivery in adult animals is highlyeffective for AAV-mediated gene delivery throughout the spinal cord andsupraspinal motor centers.

参考文献：

Bravo-Hernandez et al (2019). Spinal subpial delivery ofAAV9 enables widespread gene silencing and blocks motoneuron degeneration inALS. Nat Med. 2019 Dec 23.

2. Cell— Annexin A11是RNA颗粒和溶酶体相互作用并转运的关键调控蛋白

英文摘要：

Long-distanceRNA transport enables local protein synthesis at metabolically-active sitesdistant from the nucleus. This process ensures an appropriate spatialorganization of proteins, vital to polarized cells such as neurons. Here, wepresent a mechanism for RNA transport in which RNA granules"hitchhike" on moving lysosomes. In vitro biophysical modeling,live-cell microscopy, and unbiased proximity labeling proteomics reveal thatannexin A11 (ANXA11), an RNA granule-associated phosphoinositide-bindingprotein, acts as a molecular tether between RNA granules and lysosomes. ANXA11possesses an N-terminal low complexity domain, facilitating its phaseseparation into membraneless RNA granules, and a C-terminal membrane bindingdomain, enabling interactions with lysosomes. RNA granule transport requiresANXA11, and amyotrophic lateral sclerosis(ALS)-associated mutations in ANXA11 impair RNA granule transport by disruptingtheir interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transportby tethering RNA granules to actively-transported lysosomes, performing acritical cellular function that is disrupted in ALS.

参考文献：

Liao et al (2019). RNA Granules Hitchhike on Lysosomesfor Long-Distance Transport, Using Annexin A11 as a Molecular Tether. Cell.2019 Sep 19;179(1):147-164.e20.

3. Nature—肠道微生物可能也在ALS的病理生理过程中扮演重要角色

英文摘要：

Amyotrophic lateral sclerosis (ALS) is a complexneurodegenerative disorder, in which the clinical manifestations may beinfluenced by genetic and unknown environmental factors. Here we show thatALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic,vivarium-dependent dysbiosis and altered metabolite configuration, coupled withan exacerbated disease under germ-free conditions or after treatment withbroad-spectrum antibiotics. We correlate eleven distinct commensal bacteria atour vivarium with the severity of ALS in mice, and by their individualsupplementation into antibiotic-treated Sod1-Tg mice we demonstrate thatAkkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroidesdistasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that areadministered AM are found to accumulate AM-associated nicotinamide in thecentral nervous system, and systemic supplementation of nicotinamide improvesmotor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice.In humans, we identify distinct microbiome and metaboliteconfigurations-including reduced levels of nicotinamide systemically and in thecerebrospinal fluid-in a small preliminary study that compares patients withALS with household controls. We suggest that environmentally drivenmicrobiome-brain interactions may modulate ALS in mice, and we call for similarinvestigations in the human form of the disease.

参考文献：

Blacher et al (2019). Potential roles of gut microbiomeand metabolites in modulating ALS in mice. Nature. 2019 Aug;572(7770):474-480.

4. Science—研究揭示ALS分子病理的时空动力学特征

英文摘要：

Paralysisoccurring in amyotrophic lateral sclerosis (ALS)results from denervation of skeletal muscle as a consequence of motor neurondegeneration. Interactions between motor neurons and glia contribute to motorneuron loss, but the spatiotemporal ordering of molecular events that drivethese processes in intact spinal tissue remains poorly understood. Here, we usespatial transcriptomics to obtain gene expression measurements of mouse spinalcords over the course of disease, as well as of postmortem tissue from ALSpatients, to characterize the underlying molecular mechanisms in ALS. Weidentify pathway dynamics, distinguish regional differences between microgliaand astrocyte populations at early time points, and discern perturbations inseveral transcriptional pathways shared between murine models of ALS and humanpostmortem spinal cords.

参考文献：

Maniatiset al (2019). Spatiotemporal dynamics of molecular pathology in amyotrophiclateral sclerosis.

Science.2019 Apr 5;364(6435):89-93.

5. Science—异染色质异常和双链RNA积累介导了C9orf72多聚（PR）毒性

英文摘要：

Howhexanucleotide GGGGCC (G₄C₂) repeat expansions in C9orf72cause frontotemporal dementia (FTD) and amyotrophiclateral sclerosis (ALS) is not understood. We developed a mouse modelengineered to express poly(PR), a proline-arginine (PR) dipeptide repeatprotein synthesized from expanded G₄C₂ repeats. Theexpression of green fluorescent protein-conjugated (PR)₅₀ (a50-repeat PR protein) throughout the mouse brain yielded progressive brainatrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminatingin motor and memory impairments. We found that poly(PR) bound DNA, localized toheterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phasedisruptions, decreases in HP1α expression, abnormal histone methylation, andnuclear lamina invaginations. These aberrations of histone methylation, lamins,and HP1α, which regulate heterochromatin structure and gene expression, wereaccompanied by repetitive element expression and double-stranded RNAaccumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute tothe pathogenesis of C9orf72-associated FTD and ALS.

参考文献：

Zhang et al (2019). Heterochromatin anomalies anddouble-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science.2019 Feb 15;363(6428).

6. Cell stem cell—mir-17～92是运动神经元变性的预后标志物，也是ALS的潜在治疗靶点

英文摘要：

Progressivedegeneration of motor neurons (MNs) is the hallmark of amyotrophiclateral sclerosis (ALS). Limb-innervating lateralmotor column MNs (LMC-MNs) seem to be particularly vulnerable and are among thefirst MNs affected in ALS. Here, we report association of this differentialsusceptibility with reduced expression of the mir-17～92 cluster inLMC-MNs prior to disease onset. Reduced mir-17～92 is accompanied by elevatednuclear PTEN in spinal MNs of presymptomatic SOD1^G93A mice.Selective dysregulation of the mir-17～92/nuclear PTEN axis indegenerating SOD1^G93A LMC-MNs was confirmed in a double-transgenicembryonic stem cell system and recapitulated in human SOD1^+/L144F-inducedpluripotent stem cell (iPSC)-derived MNs. We further show that overexpressionof mir-17～92 significantly rescues human SOD1^+/L144FMNs, and intrathecal delivery of adeno-associated virus (AAV)9-mir-17～92improves motor deficits and survival in SOD1^G93A mice. Thus, mir-17～92may have value as a prognostic marker of MN degeneration and is a candidatetherapeutic target in SOD1-linked ALS.

参考文献：

Tung et al (2019). Mir-17～92 ConfersMotor Neuron Subtype Differential Resistance to ALS-Associated Degeneration. CellStem Cell. 2019 Aug 1;25(2):193-209.

7. Nat Cell Biol— UBQLN2和UBQLN4编码蛋白Ubiquilins通过mTOR信号通路和溶酶体酸化调控自噬流

英文摘要：

Althoughthe aetiology of amyotrophic lateral sclerosis(ALS) remains poorly understood, impaired proteostasis is a common feature ofdifferent forms of ALS. Mutations in genes encoding ubiquilins, UBQLN2 andUBQLN4, cause familial ALS. The role of ubiquilins in proteasomal degradationis well established, but their role in autophagy-lysosomal clearance is poorlydefined. Here, we describe a crosstalk between endoplasmic reticulum stress,mTOR signalling and autophagic flux in Drosophila and mammalian cells lackingubiquilins. We found that loss of ubiquilins leads to endoplasmic reticulumstress, impairs mTORC1 activity, promotes autophagy and causes the demise ofneurons. We show that ubiquilin mutants display defective autophagic flux dueto reduced lysosome acidification. Ubiquilins are required to maintain properlevels of the V0a/V100 subunit of the vacuolar H⁺-ATPase andlysosomal pH. Feeding flies acidic nanoparticles alleviates defectiveautophagic flux in ubiquilin mutants. Hence, our studies reveal a conservedrole for ubiquilins as regulators of autophagy by controlling vacuolar H⁺-ATPaseactivity and mTOR signalling.

参考文献：

Şentürk et al (2019). Ubiquilins regulate autophagic fluxthrough mTOR signalling and lysosomal acidification. Nat Cell Biol. 2019Mar;21(3):384-396.

8. Nat Neurosci—研究首次表明不同磷酸化TDP-43聚集体的构象和其神经毒性及疾病时程相关

英文摘要：

Accumulationof abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affectedneurons of people with amyotrophic lateral sclerosis(ALS) and frontotemporal lobar degeneration (FTLD). Morphological diversity andneuroanatomical distribution of pTDP-43 accumulations allowed classification ofFTLD cases into at least four subtypes, which are correlated with clinicalpresentations and genetic causes. To understand the molecular basis of thisheterogeneity, we developed SarkoSpin, a new method for biochemical isolationof pathological TDP-43. By combining SarkoSpin with mass spectrometry, werevealed proteins beyond TDP-43 that become abnormally insoluble in a diseasesubtype-specific manner. We show that pTDP-43 extracted from brain forms stableassemblies of distinct densities and morphologies that are associated withdisease subtypes. Importantly, biochemically extracted pTDP-43 assembliesshowed differential neurotoxicity and seeding that were correlated with diseaseduration of FTLD subjects. Our data are consistent with the notion that diseaseheterogeneity could originate from alternate pathological TDP-43 conformations,which are reminiscent of prion strains.

参考文献：

Laferrièreet al (2019). TDP-43 extracted from frontotemporal lobar degeneration subjectbrains displays distinct aggregate assemblies and neurotoxic effects reflectingdisease progression rates. Nat Neurosci. 2019 Jan;22(1):65-77.

9.Neuron—靶向于RAN蛋白的抗体可逆转C9orf72小鼠模型的C9ALS/FTD表型

英文摘要：

The intronicC9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, producessense- and antisense-expansion RNAs and six dipeptide repeat-associated,non-ATG (RAN) proteins, but their roles in disease are unclear. We generatedhigh-affinity human antibodies targeting GA or GP RAN proteins. Theseantibodies cross the blood-brain barrier and co-localize with intracellular RANaggregates in C9-ALS/FTD BAC mice. In cells, α-GA1interacts with TRIM21, andα-GA1 treatment reduced GA levels, increased GA turnover, and decreased RANtoxicity and co-aggregation of proteasome and autophagy proteins to GAaggregates. In C9-BAC mice, α-GA1reduced GA as well as GP and GR proteins,improved behavioral deficits, decreased neuroinflammation andneurodegeneration, and increased survival. Glycosylation of the Fc region ofα-GA1 is important for cell entry and efficacy. These data demonstrate that RANproteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a noveltherapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

参考文献：

Nguyen et al (2019). Antibody Therapy TargetingRANProteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron. 2019Dec4. pii: S0896-6273(19)30970-5.

10. Nat Struct Mol Biol—冷冻电镜结构研究揭示TDP-43从可逆的聚集形态过度到不可逆的聚集形态的关键变构机制

英文摘要：

TheDNA and RNA processing protein TDP-43 undergoes both functional and pathogenicaggregation. Functional TDP-43 aggregates form reversible, transient speciessuch as nuclear bodies, stress granules, and myo-granules. Pathogenic,irreversible TDP-43 aggregates form in amyotrophiclateral sclerosis and other neurodegenerative conditions. Here we findthe features of TDP-43 fibrils that confer both reversibility andirreversibility by determining structures of two segments reported to be thepathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), whichforms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues286-331 containing the amyotrophic lateral sclerosishereditary mutation A315E), which forms R-shaped folds. Energetic analysissuggests that the dagger-shaped polymorphs represent irreversible fibrilstructures, whereas the SegB polymorph may participate in both reversible andirreversible fibrils. Our structures reveal the polymorphic nature of TDP-43and suggest how the A315E mutation converts the R-shaped polymorph to anirreversible form that enhances pathology.

参考文献：

Caoet al (2019). Cryo-EM structures of four polymorphic TDP-43 amyloid cores. NatStruct Mol Biol. 2019 Jul;26(7):619-627.

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

8. 年终盘点：2019年神经炎症领域十大基础研究进展

9. 年终盘点：2019年神经活动记录十大基础研究进展

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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