Apo-opsin exists in equilibrium between a predominant inactive and a rare highly active state

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 1

Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization

The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin’s stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higher-order organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration

A Naturally Occurring Mutation of the Opsin Gene (T4R) in Dogs Affects Glycosylation and Stability of the G Protein-Coupled Receptor

Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHOT4R/T4R dog retina, we found that the mutation abolished glycosylation at Asn2, whereas glycosylation at Asn15 was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho* lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (Gt). Structurally, the mutation affected mainly the “plug” at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity

The Perfect Number Theorem and Wilson's Theorem

This article formalizes proofs of some elementary theorems of number theory (see [1, 26]): Wilson's theorem (that n is prime iff n > 1 and (n - 1)! ≅ -1 (mod n)), that all primes (1 mod 4) equal the sum of two squares, and two basic theorems of Euclid and Euler about perfect numbers. The article also formally defines Euler's sum of divisors function Φ, proves that Φ is multiplicative and that Σ k|n Φ(k) = n.Casella Postale 49, 54038 Montignoso, ItalyM. Aigner and G. M. Ziegler. Proofs from THE BOOK. Springer-Verlag, Berlin Heidelberg New York, 2004.Grzegorz Bancerek. Cardinal numbers. Formalized Mathematics, 1(2):377-382, 1990.Grzegorz Bancerek. The fundamental properties of natural numbers. Formalized Mathematics, 1(1):41-46, 1990.Grzegorz Bancerek. König's theorem. Formalized Mathematics, 1(3):589-593, 1990.Grzegorz Bancerek. The ordinal numbers. Formalized Mathematics, 1(1):91-96, 1990.Grzegorz Bancerek and Krzysztof Hryniewiecki. Segments of natural numbers and finite sequences. Formalized Mathematics, 1(1):107-114, 1990.Józef Białas. Infimum and supremum of the set of real numbers. Measure theory. Formalized Mathematics, 2(1):163-171, 1991.Czesław Byliński. Basic functions and operations on functions. Formalized Mathematics, 1(1):245-254, 1990.Czesław Byliński. The complex numbers. Formalized Mathematics, 1(3):507-513, 1990.Czesław Byliński. Finite sequences and tuples of elements of a non-empty sets. Formalized Mathematics, 1(3):529-536, 1990.Czesław Byliński. Functions and their basic properties. Formalized Mathematics, 1(1):55-65, 1990.Czesław Byliński. Functions from a set to a set. Formalized Mathematics, 1(1):153-164, 1990.Czesław Byliński. Partial functions. Formalized Mathematics, 1(2):357-367, 1990.Czesław Byliński. Some basic properties of sets. Formalized Mathematics, 1(1):47-53, 1990.Czesław Byliński. The sum and product of finite sequences of real numbers. Formalized Mathematics, 1(4):661-668, 1990.Agata Darmochwał. Finite sets. Formalized Mathematics, 1(1):165-167, 1990.Yoshinori Fujisawa and Yasushi Fuwa. The Euler's function. Formalized Mathematics, 6(4):549-551, 1997.Yoshinori Fujisawa, Yasushi Fuwa, and Hidetaka Shimizu. Public-key cryptography and Pepin's test for the primality of Fermat numbers. Formalized Mathematics, 7(2):317-321, 1998.Krzysztof Hryniewiecki. Basic properties of real numbers. Formalized Mathematics, 1(1):35-40, 1990.Krzysztof Hryniewiecki. Recursive definitions. Formalized Mathematics, 1(2):321-328, 1990.Magdalena Jastrzebska and Adam Grabowski. On the properties of the Möbius function. Formalized Mathematics, 14(1):29-36, 2006, doi:10.2478/v10037-006-0005-0.Artur Korniłowicz and Piotr Rudnicki. Fundamental Theorem of Arithmetic. Formalized Mathematics, 12(2):179-186, 2004.Jarosław Kotowicz and Yuji Sakai. Properties of partial functions from a domain to the set of real numbers. Formalized Mathematics, 3(2):279-288, 1992.Rafał Kwiatek. Factorial and Newton coefficients. Formalized Mathematics, 1(5):887-890, 1990.Rafał Kwiatek and Grzegorz Zwara. The divisibility of integers and integer relative primes. Formalized Mathematics, 1(5):829-832, 1990.W. J. LeVeque. Fundamentals of Number Theory. Dover Publication, New York, 1996.Takaya Nishiyama and Yasuho Mizuhara. Binary arithmetics. Formalized Mathematics, 4(1):83-86, 1993.Beata Padlewska. Families of sets. Formalized Mathematics, 1(1):147-152, 1990.Piotr Rudnicki. Little Bezout theorem (factor theorem). Formalized Mathematics, 12(1):49-58, 2004.Piotr Rudnicki and Andrzej Trybulec. Abian's fixed point theorem. Formalized Mathematics, 6(3):335-338, 1997.Piotr Rudnicki and Andrzej Trybulec. Multivariate polynomials with arbitrary number of variables. Formalized Mathematics, 9(1):95-110, 2001.Andrzej Trybulec. Binary operations applied to functions. Formalized Mathematics, 1(2):329-334, 1990.Andrzej Trybulec. Tuples, projections and Cartesian products. Formalized Mathematics, 1(1):97-105, 1990.Andrzej Trybulec. On the sets inhabited by numbers. Formalized Mathematics, 11(4):341-347, 2003.Andrzej Trybulec and Czesław Byliński. Some properties of real numbers. Formalized Mathematics, 1(3):445-449, 1990.Michał J. Trybulec. Integers. Formalized Mathematics, 1(3):501-505, 1990.Wojciech A. Trybulec. Non-contiguous substrings and one-to-one finite sequences. Formalized Mathematics, 1(3):569-573, 1990.Zinaida Trybulec. Properties of subsets. Formalized Mathematics, 1(1):67-71, 1990.Edmund Woronowicz. Relations and their basic properties. Formalized Mathematics, 1(1):73-83, 1990.Edmund Woronowicz. Relations defined on sets. Formalized Mathematics, 1(1):181-186, 1990.Hiroshi Yamazaki, Yasunari Shidama, and Yatsuka Nakamura. Bessel's inequality. Formalized Mathematics, 11(2):169-173, 2003

Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP

Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP

Structural approaches to understanding retinal proteins needed for vision.

The past decade has witnessed an impressive expansion of our knowledge of retinal photoreceptor signal transduction and the regulation of the visual cycle required for normal eyesight. Progress in human genetics and next generation sequencing technologies have revealed the complexity behind many inherited retinal diseases. Structural studies have markedly increased our understanding of the visual process. Moreover, technical innovations and improved methodologies in proteomics, macromolecular crystallization and high resolution imaging at different levels set the scene for even greater advances. Pharmacology combined with structural biology of membrane proteins holds great promise for developing innovative accessible therapies for millions robbed of their sight or progressing toward blindness