Human-to-mouse prion-like propagation of mutant huntingtin protein

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell-autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1582-9) contains supplementary material, which is available to authorized users.

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

“…Later, the formation of aggregates was evaluated using the same cells (HD72-iPSC-derived neural precursors) a short time after transplantation, and no evidence of aggregates was found in the mouse transgenic model. Recently, Jeon et al [119] performed more studies and confirmed that the mutant HTT protein derived from NPCs generated from iPSC-HD is able to proliferate in vivo in fetal host tissue. They associated this effect to the activity of exosomes, since it has been demonstrated in vivo and in vitro that exosomes can transport mutant Htt.…”

“…However, more recent publications suggested that the pathology does not occur purely at the cellular level. Observation of aggregates of mutant HTT within fetal striatal allografts in patients with HD provides strong evidence for the existence of a non-cell-autonomous mechanism of action, which accounts for the HTT protein to spread via pathological cell-cell communication [119,121].…”

“…However, autologous HD-iPSCs are not a good choice for stem cell-based therapy since they carry the HD mutation, which compromises such therapy [69,119]. Thus, transplantation of HD72-iPSCderived neural precursors, where HD72 is the number of CAG repeats, into a QA rat model showed that a long time after transplantation (33 weeks), grafted cells showed the formation of huntingtin aggregates.…”

PeripheralHttsilencing does not ameliorate central signs of disease in the B6.HttQ111/+mouse model of Huntington’s Disease

“…This mechanism is supported by the markedly reduced risk of sporadic PD in patients undergoing vagotomy [26], and the ability of fibrillar alpha-synuclein to travel from the gut to the brainstem of experimental animals [27]. Similar prion like spreading has been proposed in HD -transplantation of human HD fibroblasts into the ventricles of wild-type animals results in the formation of mutant Huntingtin aggregates in wild-type cells [28]. In short, peripheral silencing of neurodegenerative disease proteins has the potential to impact disease progression.…”

Mutant huntingtin protein expression and blood–spinal cord barrier dysfunction in huntington disease

“…However, mHTT is not always found inside cellular compartments, but is also present outside the cell boundary, notably in the cerebrospinal fluid, plasma, and extracellular matrix. [2][3][4][5][6] The HD gene product is further expressed outside the CNS, leading to peripheral pathology. 7,8 In theory, mHTT aggregates should be found in every tissue and cell type of the body, but their presence/ location within the spinal cord and their pathological significance at this site have not been investigated, and this includes effects on the blood-spinal cord barrier (BSCB).…”