Molecular Bases of Neurodegenerative Disorders of the Retina

Cilia are microtubule-based extensions of the plasma membrane of cells. These extensions detect extrinsic cues that are crucial for carrying out a myriad of developmental and homeostatic signaling cascades. Cilia have evolved diverse means to mediate signaling cascades in a cell-type specific manner. In this article, I have summarized the conserved mechanisms of formation of cilia and their structural and functional specialization for light detection.

Ciliopathies refer to a genetically and clinically heterogeneous class of disorders that result from defects in the formation or function of the primary cilium. Cilia are the microtubule-based organelles that protrude from the surface of almost all vertebrate cells, including the rod and cone photoreceptors. The photoreceptor sensory cilium consists of the connecting cilium and outer segment with the outer segment forming a unique structure containing thousands of tightly packed disc membranes. Mutations in over 50 genes result in syndromic ciliopathies that can manifest with retinal degeneration, including Bardet-Biedl syndrome (BBS), Joubert Syndrome, Jeune Syndrome, and nephronophthisis (NPHP) or in non-syndromic retinal dystrophies like Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). Zebrafish have been widely used as a model system to study ciliopathies, particularly BBS and Joubert Syndrome, and for studying the mechanisms leading to photoreceptor degeneration associated with these disorders. Investigators were drawn to zebrafish due to the rapid growth and transparency of the zebrafish embryo, the differentiation of photoreceptors by 3 days post-fertilization, and the ability to suppress gene function through morpholino knockdown. The genetic heterogeneity of ciliopathies and desire for more accurate genotype-phenotype correlations make zebrafish an appealing model for studying gene- and allele-specific differences in a rapid manner. This review will discuss the current zebrafish models of retinal ciliopathies, evaluate the widespread use of morpholinos as tools to knock down gene function in zebrafish, and make predictions on how zebrafish will contribute in future studies of ciliopathies.

Phosphoinositides are phospholipids that regulate signal transduction, endocytosis, and protein trafficking. Each phosphoinositide has a unique pattern of distribution within cellular compartments and is tightly regulated by inositol kinases and phosphatases localized within a specific membrane compartment. Inositol polyphosphate 5-phosphatases regulate phosphoinositide levels and are implicated in human diseases, such as Lowe syndrome and Joubert syndrome. Here we review the pertinent findings of the roles of 5-phosphatases in cilia function and signaling.

Diabetic Retinopathy (DR) is the leading cause of irreversible global vision loss. It affects the entire neurovascular unit of the retina, along with gradual neurodegeneration and neuroinflammation. DR has primarily been considered a microvasculature complication of diabetes, a well-known metabolic disorder. However, recent studies have reported the presence of neurodegenerative changes in the retina of DR patients prior to clinical manifestations. In this review, we have compiled clinical, histopathological, biochemical and genetic evidences that suggest a role of neurodegeneration in DR progression and pathogenesis. These studies indicated neural changes in the retina that have lead to microvascular alterations. Furthermore, the mechanisms underlying the neural changes can help identify drug targets for effective management of the disease, which in turn will help reduce the burden of visual impairments caused by DR.

Homodimeric (KIF17) and heterotrimeric kinesin-2 (KIF3A, KIF3B and KAP) molecular motors are essential for anterograde intraflagellar transport (IFT) among invertebrates. Here we show that deletion of KIF3A in embryonic mouse retina interferes with IFT by preventing transition zone and axoneme formation. Absence of outer segments leads to severe mistrafficking of rhodopsin and rapid degeneration. By contrast, deletion of KIF3A in the adult mouse by tamoxifen-induction reveals normal rhodopsin transport to outer segments with failure of outer segment (OS) maintenance. Germline deletion of KIF17, a motor that cooperates with heterotrimeric kinesin-2 among invertebrates, affected neither OS structure nor photoreceptor morphology/ function thereby excluding an essential role of KIF17 in photoreceptor IFT. A KIF3A/KIF17 double knockout phenocopies a rod-specific KIF3A knockout. We conclude IFT is not required for rhodopsin transport to the OS but rather, anterograde IFT mediated by KIF3 participates in photoreceptor transition zone (PTZ) and axoneme formation.

The photoreceptor specific tetraspanin protein peripherin-2, also known as retinal degeneration slow (RDS) plays a critical role in the biogenesis and maintenance of both rod and cone photoreceptor outer segments. Over 80 pathological mutations in RDS have been linked with multiple degenerative blinding diseases including retinitis pigmentosa and various forms of macular degeneration. RDS-associated disease is characterized by a diverse set of phenotypes with variability in penetrance, severity, and timing of disease onset. Much insight into the complex pathological mechanisms associated with RDS mutations has been gleaned from work in animal models with disease-causing mutations. In the current review we summarize our current understanding of RDS function in the normal retina and how defects in this function contribute to the associated disease pathologies in human patients.

Growth factor receptor-bound protein 14 (Grb14) belongs to the Grb7 family. It is an adapter molecule, lacking any intrinsic enzyme activity, but mediates protein-protein and protein-lipid interactions. In photoreceptors, Grb14 undergoes a rhodopsin-dependent translocation from the inner segments to the outer segments. In photoreceptors, Grb14 undergoes a light-dependent tyrosine phosphorylation and protects the insulin receptor (IR) phosphorylation, which is neuroprotective. Outersegment- localized Grb14 also modulates the activity of the cyclic nucleotide gated (CNG) chancel. Thus, Grb14 plays a key role in receiving signals from rhodopsin, and translocating to outer segments, where it regulates IR and CNG channel activities. The present study supports the idea that rhodopsin regulates non-canonical signaling pathways in photoreceptor cells.

The cone photoreceptor-specific cyclic nucleotide-gated (CNG) channel is indispensable for cone function. Cones are essential for daylight vision and visual acuity. Mutations in the CNGA3 and CNGB3 genes are associated with achromatopsia, cone degeneration, and early-onset macular degeneration, and account for 80-85% of Achromatopsia cases. Patients with CNG channel defects exhibit cone dysfunction and progressive degeneration of cones, as revealed by electrophysiological recordings, psychophysical testing, and morphological examinations. The cellular events and underlying mechanisms of CNG channel deficiency have been explored using mouse models. In this review, we have summarized our current understanding of the modes of cone defects due to CNG channel deficiency.