一. 《Nature medicine》和《Cell》：C9orf72致病新机制被揭示—多聚GR二肽重复扩增损害蛋白翻译和应激颗粒动力学，而应激颗粒还具有破坏核质运输过程的负面作用。最后，神经元形成的多聚GA异常聚集体可以募集蛋白酶体。
摘要：The major genetic cause of frontotemporaldementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion1,2.Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicityfrom repeat-containing RNA and from dipeptide repeat proteins translated fromthese transcripts. To investigate the contribution of poly(GR) dipeptide repeatproteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generatedmice that expressed GFP-(GR)100 inthe brain.GFP-(GR)100 micedeveloped age-dependent neurodegeneration, brain atrophy,and motor and memory deficits through the accumulation of diffuse, cytoplasmicpoly(GR). Poly(GR) co-localized with ribosomal subunits and the translationinitiation factor eIF3η in GFP-(GR)100 mice and, of importance, in c9FTD/ALSpatients. Combined with the differential expression of ribosome-associatedgenes in GFP-(GR)100 mice,these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed,poly(GR) inhibited canonical and non-canonical protein translation in HEK293Tcells, and also induced the formation of stress granules and delayed theirdisassembly. These data suggest that poly(GR) contributes to c9FTD/ALS byimpairing protein translation and stress granule dynamics, consequently causingchronic cellular stress and preventing cells from mounting an effective stressresponse. Decreasing poly(GR) and/or interrupting interactions between poly(GR)and ribosomal and stress granule-associated proteins may thus representpotential therapeutic strategies to restore homeostasis.
1.Poly(GR) impairs protein translation and stress granule dynamics inC9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.Nat Med. 2018 Aug;24(8):1136-1142.
2.Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018 May3;173(4):958-971.e17.
3.In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals ProteasomeRecruitment. Cell. 2018 Feb 8;172(4):696-705.e12.
4.Context-Dependent and Disease-Specific Diversity in Protein Interactions withinStress Granules. Cell. 2018 Jan 25;172(3):590-604.
摘要：The diversity and complexity of the human brain are widelyassumed to be encoded within a constant genome. Somatic gene recombination,which changes germline DNA sequences to increase molecular diversity, couldtheoretically alter this code but has not been documented in the brain, to ourknowledge. Here we describe recombination of the Alzheimer's disease-relatedgene APP, which encodes amyloid precursor protein, in human neurons, occurringmosaically as thousands of variant 'genomic cDNAs' (gencDNAs). gencDNAs lackedintrons and ranged from full-length cDNA copies of expressed, brain-specificRNA splice variants to myriad smaller forms that contained intra-exonicjunctions, insertions, deletions, and/or single nucleotide variations. DNA insitu hybridization identified gencDNAs within single neurons that were distinctfrom wild-type loci and absent from non-neuronal cells. Mechanistic studiessupported neuronal 'retro-insertion' of RNA to produce gencDNAs; this processinvolved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadicAlzheimer's disease showed increased gencDNA diversity, including elevenmutations known to be associated with familial Alzheimer's disease that wereabsent from healthy neurons. Neuronal gene recombination may allow'recording' of neural activity for selective 'playback' of preferred genevariants whose expression bypasses splicing; this has implications for cellulardiversity, learning and memory, plasticity, and diseases of the human brain.
参考文献：Somatic APP gene recombination inAlzheimer's disease and normal neurons. Nature. 2018 Nov;563(7733):639-645.
摘要：We previously reported1 thepresence of amyloid-β protein (Aβ) deposits in individuals withCreutzfeldt-Jakob disease (CJD)who had been treated during childhood with human cadaveric pituitary-derivedgrowth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aβ in theserelatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), incontrast to other prion-disease patientsand population controls, allied with the ability of Alzheimer'sdisease brain homogenatesto seed Aβ deposition in laboratory animals, led us to argue that theimplicated c-hGH batches might have been contaminated with Aβ seeds as well aswith prions. However, this was necessarily an association, and not anexperimental, study in humans and causality could not be concluded. Given thepublic health importance of our hypothesis, we proceeded to identify andbiochemically analyse archived vials of c-hGH. Here we show that certain c-hGHbatches to which patients with iCJD and Aβ pathology were exposed havesubstantial levels of Aβ40, Aβ42 and tau proteins, and that thismaterial can seed the formation of Aβ plaques and cerebral Aβ-amyloidangiopathy in intracerebrally inoculated mice expressing a mutant, humanizedamyloid precursor protein. These results confirm the presence of Aβ seeds inarchived c-hGH vials and are consistent with the hypothesized iatrogenic humantransmission of Aβ pathology. This experimental confirmation has implicationsfor both the prevention and the treatment of Alzheimer's disease, and should prompt a review of therisk of iatrogenic transmission of Aβ seeds by medical and surgical procedureslong recognized to pose a risk of accidental prion transmission2,3.
参考文献：Transmission of amyloid-β protein pathologyfrom cadaveric pituitary growth hormone. Nature. 2018 Dec;564(7736):415-419.
四. 《Nature medicine》：探究发现与神经变性痴呆相关的保守基因网络。
Identifying themechanisms through which genetic risk causes dementia is an imperative for newtherapeutic development. Here, we apply a multistage, systems biology approachto elucidate the disease mechanisms in frontotemporal dementia. We identify twogene coexpression modules that are preserved in mice harboring mutations inMAPT, GRN and other dementia mutations on diverse genetic backgrounds. Webridge the species divide via integration with proteomic and transcriptomicdata from the human brain to identify evolutionarily conserved,disease-relevant networks. We find that overexpression of miR-203, a hub of aputative regulatory microRNA (miRNA) module, recapitulates mRNA coexpressionpatterns associated with disease state and induces neuronal cell death,establishing this miRNA as a regulator of neurodegeneration. Using a databaseof drug-mediated gene expression changes, we identify small molecules that can normalizethe disease-associated modules and validate this experimentally. Our resultshighlight the utility of an integrative, cross-species network approach to drugdiscovery.
参考文献：Identification of evolutionarily conservedgene networks mediating neurodegenerative dementia. Nat Med. 2018 Dec 3.
Harnessing thepotential of human stem cells for modeling the physiology and diseases ofcortical circuitry requires monitoring cellular dynamics in vivo. We show thathuman induced pluripotent stem cell (iPSC)-derived cortical neuronstransplanted into the adult mouse cortex consistently organized into large (upto ~100 mm3) vascularized neuron-glia territories with complexcytoarchitecture. Longitudinal imaging of >4000 grafted developing humanneurons revealed that neuronal arbors refined via branch-specific retraction;human synaptic networks substantially restructured over 4 months, with balancedrates of synapse formation and elimination; and oscillatory population activitymirrored the patterns of fetal neural networks. Lastly, we found increasedsynaptic stability and reduced oscillations in transplants from two individualswith Down syndrome, demonstrating the potential of in vivo imaging in humantissue grafts for patient-specific modeling of cortical development,physiology, and pathogenesis.
参考文献：In vivo modeling of human neuron dynamicsand Down syndrome. Science. 2018 Nov 16;362(6416).
六. 《Nature》：研究发现Pick小体中含有的tau蛋白构像为3R tau。
The orderedassembly of tau protein into abnormal filamentous inclusions underlies manyhuman neurodegenerative diseases1. Tau assemblies seem to spread throughspecific neural networks in each disease2, with short filaments having thegreatest seeding activity3. The abundance of tau inclusions strongly correlateswith disease symptoms4. Six tau isoforms are expressed in the normal adulthuman brain-three isoforms with four microtubule-binding repeats each (4R tau)and three isoforms that lack the second repeat (3R tau)1. In various diseases,tau filaments can be composed of either 3R or 4R tau, or of both. Tau filamentshave distinct cellular and neuroanatomical distributions5, with morphological andbiochemical differences suggesting that they may be able to adoptdisease-specific molecular conformations6,7. Such conformers may give rise todifferent neuropathological phenotypes8,9, reminiscent of prion strains10.However, the underlying structures are not known. Using electroncryo-microscopy, we recently reported the structures of tau filaments frompatients with Alzheimer's disease, which contain both 3R and 4R tau11. Here wedetermine the structures of tau filaments from patients with Pick's disease, aneurodegenerative disorder characterized by frontotemporal dementia. Thefilaments consist of residues Lys254-Phe378 of 3R tau, which are foldeddifferently from the tau filaments in Alzheimer's disease, establishing theexistence of conformers of assembled tau. The observed tau fold in thefilaments of patients with Pick's disease explains the selective incorporationof 3R tau in Pick bodies, and the differences in phosphorylation relative tothe tau filaments of Alzheimer's disease. Our findings show how tau can adoptdistinct folds in the human brain in different diseases, an essential step forunderstanding the formation and propagation of molecular conformers.
参考文献：Structures of filaments from Pick's diseasereveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140.
Aging is a major risk factor forboth genetic and sporadic neurodegenerative disorders. However, it is unclearhow aging interacts with genetic predispositions to promote neurodegeneration.Here, we investigate how partial loss of function of TBK1, a major geneticcause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is anendogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice isdependent on RIPK1 kinase activity. In aging human brains, another endogenousRIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show thatin Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the keyhallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonaldegeneration, neuronal loss, and behavior deficits, which are blocked uponinhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1expression, which cooperates with genetic risk factors to promote the onset ofALS/FTD.
参考文献：TBK1 Suppresses RIPK1-DrivenApoptosis and Inflammation during Development and in Aging. Cell. 2018 Sep6;174(6):1477-1491.e19.
The major geneticcause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)is a C9orf72 G4C2 repeat expansion1,2. Proposed mechanisms by which theexpansion causes c9FTD/ALS include toxicity from repeat-containing RNA and fromdipeptide repeat proteins translated from these transcripts. To investigate thecontribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis ina mammalian in vivo model, we generated mice that expressed GFP-(GR)100 in thebrain. GFP-(GR)100 mice developed age-dependent neurodegeneration, brainatrophy, and motor and memory deficits through the accumulation of diffuse,cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and thetranslation initiation factor eIF3η in GFP-(GR)100 mice and, of importance, inc9FTD/ALS patients. Combined with the differential expression ofribosome-associated genes in GFP-(GR)100 mice, these findings demonstratepoly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical andnon-canonical protein translation in HEK293T cells, and also induced the formationof stress granules and delayed their disassembly. These data suggest thatpoly(GR) contributes to c9FTD/ALS by impairing protein translation and stressgranule dynamics, consequently causing chronic cellular stress and preventingcells from mounting an effective stress response. Decreasing poly(GR) and/orinterrupting interactions between poly(GR) and ribosomal and stressgranule-associated proteins may thus represent potential therapeutic strategiesto restore homeostasis.
参考文献：Poly(GR) impairs protein translation andstress granule dynamics in C9orf72-associated frontotemporal dementia andamyotrophic lateral sclerosis. Nat Med. 2018 Aug;24(8):1136-1142.
In Lewy bodydiseases-including Parkinson's disease, without or with dementia, dementia withLewy bodies, and Alzheimer's disease with Lewy body co-pathology 1 -α-synuclein(α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast,in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes asglial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Synin GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) isconformationally and biologically distinct. GCI-α-Syn forms structures that aremore compact and it is about 1,000-fold more potent than LB-α-Syn in seedingα-Syn aggregation, consistent with the highly aggressive nature of multiplesystem atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seedingα-Syn pathology, which raises the question of why they demonstrate differentcell-type distributions in Lewy body disease versus multiple system atrophy. Wefound that oligodendrocytes but not neurons transform misfolded α-Syn into aGCI-like strain, highlighting the fact that distinct α-Syn strains aregenerated by different intracellular milieus. Moreover, GCI-α-Syn maintains itshigh seeding activity when propagated in neurons. Thus, α-Syn strains aredetermined by both misfolded seeds and intracellular environments.
参考文献：Cellular milieu imparts distinctpathological α-synuclein strains in α-synucleinopathies. Nature. 2018May;557(7706):558-563.
十. 《Nature medicine》：C9orf72与自噬相关—C9orf72的单倍剂量不足引起ALS/FTD神经变性。
摘要：An intronic GGGGCC repeat expansion in C9ORF72 isthe most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia(FTD), but the pathogenic mechanism of this repeat remains unclear. Using humaninduced motor neurons (iMNs), we found that repeat-expanded C9ORF72 washaploinsufficient in ALS. We found that C9ORF72 interacted with endosomes andwas required for normal vesicle trafficking and lysosomal biogenesis in motorneurons. Repeat expansion reduced C9ORF72 expression, triggeringneurodegeneration through two mechanisms: accumulation of glutamate receptors,leading to excitotoxicity, and impaired clearance of neurotoxic dipeptiderepeat proteins derived from the repeat expansion. Thus, cooperativity betweengain- and loss-of-function mechanisms led to neurodegeneration. RestoringC9ORF72 levels or augmenting its function with constitutively active RAB5 orchemical modulators of RAB5 effectors rescued patient neuron survival and amelioratedneurodegenerative processes in both gain- and loss-of-function C9ORF72 mousemodels. Thus, modulating vesicle trafficking was able to rescueneurodegeneration caused by the C9ORF72 repeat expansion. Coupled with raremutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results revealmechanistic convergence on vesicle trafficking in ALS and FTD.
参考文献：Haploinsufficiencyleads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. NatMed. 2018 Mar;24(3):313-325.
27、神经科学临床和基础Learning & Memory亚群；