To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.

SUMMARY Huntington’s disease like-2 (HDL2) is a phenocopy of Huntington’s disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a novel promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein. Importantly, BAC-HDL2 but not control BAC mice accumulate polyQ-containing NIs in a pattern strikingly similar to those in the patients. Furthermore, BAC mice with genetic silencing of the expanded CUG transcript still express HDL2-CAG transcript and manifest polyQ pathogenesis. Finally, studies of HDL2 mice and patients revealed CBP sequestration into NIs and evidence for interference of CBP-mediated transcriptional activation. These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2

Intervertebral disc degeneration usually starts from the inner nucleus pulposus (NP). The majority of previous NP-related studies assessed the outcome by the expression of chondrogenic markers since NP cells are chondrocyte like. However, NP cells are unique from chondrocytes and such assessments may be inappropriate. Very recently, several investigators published their findings about the transcriptional differences between NP cells and other related cell types on a genomic scale. In this review we discuss these recent findings and summarize the molecules that may be utilized as NP-specific markers to distinguish normal NP cells from several cell types and as markers that indicate its degeneration. We will revisit markers that distinguish NP cells from the outer surrounding annulus fibrosus (AF) cells and articular chondrocytes so as to facilitate authentic NP cell engineering from stem cells. Our review indicated that N-cadherin and keratin 19 have the potential to serve as common NP markers, as they distinguish healthy NP cells from AF cells, articular cartilage cells and degenerated NP cells.

Intervertebral disc degeneration is associated with back pain and radiculopathy which, being a leading cause of disability, seriously affects the quality of life and presents a hefty burden to society. There is no effective intervention for the disease and the etiology remains unclear. Here, we show that disc degeneration exhibits features of fibrosis in humans and confirmed this in a puncture-induced disc degeneration (PDD) model in rabbit. Implantation of bone marrow-derived mesenchymal stem cells (MSCs) to PDD discs can inhibit fibrosis in the nucleus pulposus with effective preservation of mechanical properties and overall spinal function. We showed that the presence of MSCs can suppress abnormal deposition of collagen I in the nucleus pulposus, modulating profibrotic mediators MMP12 and HSP47, thus reducing collagen aggregation and maintaining proper fibrillar properties and function. As collagen fibrils can regulate progenitor cell activities, our finding provides new insight to the limited self-repair capability of the intervertebral disc and importantly the mechanism by which MSCs may potentiate tissue regeneration through regulating collagen fibrillogenesis in the context of fibrotic diseases.